Methods of using MEK inhibitors

ABSTRACT

The present invention provides methods of treating cancer by administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with other cancer treatments.

CROSS-REFERENCE TO RELATED APPLICATIONS

The applicants claim priority under 35 U.S.C. 119(e) to Provisional Application No. 60/875,412 filed on Dec. 14, 2006, the disclosure of which are incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods of treating cancer with a compound that inhibits protein kinase enzymatic activity and the resultant modulation of cellular activities (such as proliferation, differentiation, programmed cell death, migration, chemoinvasion and metabolism) in combination with anticancer agents.

2. State of the Art

Improvements in the specificity of agents used to treat various disease states such as cancer, metabolic, and inflammatory diseases is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms.

Protein kinases are enzymes that catalyze the phosphorylation of proteins at the hydroxy groups of tyrosine, serine and threonine residues of proteins. The kinase complement of the human genome contains 518 putative protein kinase genes (Manning et al, Science, (2002), 298, 1912). The consequences of this activity include effects on cell differentiation, proliferation, transcription, translation, metabolism, cell cycle progression, apoptosis, metabolism, cytoskeletal rearrangement and movement; i.e., protein kinases mediate the majority of signal transduction in eukaryotic cells. Furthermore, abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to cancer. Chromosomal mapping has revealed that over 200 kinases map to disease loci; including cancer, inflammatory and metabolic disease.

Tyrosine kinases can be categorized as receptor type or non-receptor type. Receptor-type tyrosine kinases have an extracellular, a transmembrane, and an intracellular portion, while non-receptor type tyrosine kinases are wholly intracellular.

Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified. One tyrosine kinase subfamily, designated the HER subfamily, is comprised of EGFR (HER1), HER2, HER3, and HER4. Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, and IR-R. The PDGF subfamily includes the PDGF-alpha and -beta receptors, CSFIR, c-kit and FLK-II. Then there is the FLK family, which is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (Flt-1). The PDGF and FLK families are usually considered together due to the similarities of the two groups. For a detailed discussion of the receptor-type tyrosine kinases, see Plowman et al. (1994) DN&P 7(6): 334-339, which is hereby incorporated by reference.

The non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, Abl, Syk/Zap70, Fes/Fps, Fak, Jak, and Ack. Each of these subfamilies is further sub-divided into varying receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. For a more detailed discussion of the non-receptor type of tyrosine kinases, see Bolen (1993) Oncogene, 8:2025-2031, which is hereby incorporated by reference.

Serine-threonine kinases play critical roles in intracellular signal transduction and include multiple families, such as STE, CKI, AGC, CAMK, and CMGC. Important subfamilies include, the MAP kinases, p38, JNK and ERK, which modulate signal transduction resulting from such diverse stimuli as mitogenic, stress, proinflammatory and antiapoptotic pathways. Members of the MAP kinase subfamily have been targeted for therapeutic intervention, including p38a, JNK isozymes and Raf.

Since protein kinases and their ligands play critical roles in various cellular activities, deregulation of protein kinase enzymatic activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer. In addition to oncological indications, altered kinase signaling is implicated in numerous other pathological diseases, such as immunological disorders, metabolic and cardiovascular diseases, inflammatory diseases, and degenerative diseases. Therefore, both receptor and non-receptor protein kinases are attractive targets for small molecule drug discovery.

One particularly attractive goal for therapeutic use of kinase modulation relates to oncological indications. For example, modulation of protein kinase activity for the treatment of cancer has been demonstrated successfully with the FDA approval of Gleevec® (imatinib mesylate, produced by Novartis Pharmaceutical Corporation of East Hanover, N.J.) for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma cancers. Gleevec is a selective Abl kinase inhibitor.

Modulation (particularly inhibition) of cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. Drug Disc Technol 2001 6, 1005-1024), is an attractive goal for development of small-molecule drugs. Anti-angiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with dysregulated vascularization, including ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis. As well, cell antiproliferative agents are desirable to slow or stop the growth of tumors.

One particularly attractive target for small-molecule modulation, with respect to antiangiogenic and antiproliferative activity is MEK. Inhibition of MEK1 (MAPK/ERK Kinase) is a promising strategy to control the growth of tumors that are dependent on aberrant ERK/MAPK pathway signaling (Solit et al., 2006; Wellbrock et al., 2004). The MEK-ERK signal transduction cascade is a conserved pathway which regulates cell growth, proliferation, differentiation, and apoptosis in response to growth factors, cytokines, and hormones. This pathway operates downstream of Ras which is often upregulated or mutated in human tumors. It has been demonstrated that MEK is a critical effector of Ras function. The ERKIMAPK pathway is upregulated in 30% of all tumors and oncogenic activating mutations in K-Ras and B-Raf have been identified in 22% and 18% of all cancers respectively (Allen et al., 2003; Bamford S, 2004; Davies et al., 2002; Malumbres and Barbacid, 2003). A large portion of human cancers, including 66% (B-Raf) of malignant melanomas, 60% (K-Ras) and 4% (B-Raf) of pancreatic cancers, 50% of colorectal cancers (colon, in particular, K-Ras: 30%, B-Raf: 15%), 20% (K-Ras) of lung cancers, 27% (B-Raf) papillary and anaplastic thyroid cancer, and 10-20% (B-Raf) of endometriod ovarian cancers, harbor activating Ras and Raf mutations. Other cancers that may be treatable by inhibiting the ERK/MAPK pathway include kidney cancer (Rika Hoshino, et. al. Oncogene 21 Jan. 1999, Volume 18, Number 3, Pages 813-822), breast cancer (Santen R J, et. al. Steroid Biochem Mol Biol 2002, 80239), multiple myeloma Hu L et. al. Blood 2003, 101, 3126), ovarian cancer Nicosia S V et. al. Hematol Oncol Clin North Am 2003, 17 927), and AML (Milella M et. al. Curr Pharm Des 2005, 11, 2779).

It has been shown that inhibition of the ERK pathway, and in particular inhibition of MEK kinase activity, results in anti-metastatic and anti-angiogenic effects largely due to a reduction of cell-cell contact and motility as well as downregulation of vascular endothelial growth factor (VEGF) expression. Furthermore, expression of dominant negative MEK, or ERK reduced the transforming ability of mutant Ras as seen in cell culture and in primary and metastatic growth of human tumor xenografts in vivo. Therefore, the MEK-ERK signal transduction pathway is an appropriate pathway to target for therapeutic intervention.

It is well established that combining treatments with different mechanisms of action often leads to enhanced anti-tumor activity as compared to single treatments administered alone. This is true for combinations of chemotherapies (e.g. Kyrgiou M. et. al. J Natl Cancer Inst 2006, 98, 1655) and combinations of antibodies and chemotherapy (e.g. Pasetto L M et. al. Anticancer Res 2006, 26, 3973.

SUMMARY OF THE INVENTION

The compositions of the invention are used to treat diseases associated with abnormal and or unregulated cellular activities. Disease states which can be treated by the methods and compositions provided herein include cancer. The invention is directed to methods of treating these diseases by administering a Compound of Formula I in combination with one or more treatment(s).

One aspect of the Invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt or solvate, thereof; or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier, excipient, or diluent in combination with one or more treatment(s) selected from surgery, one or more chemotherapeutic agent(s), one or more of the hormone therapy(s), one or more of the antibody(s), hypothermia therapy, radioactive iodine therapy, and radiation wherein the Compound of Formula I is that where A, X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in Group A, Group B, Group C, or Group D: Group A:

-   A is arylene optionally substituted with one, two, three or four     groups selected from R¹⁰, R¹¹, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴     and R¹⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, halo,     haloalkoxy, hydroxy, alkoxy, amino, alkylamino, dialkylamino,     haloalkyl, —NHS(O)₂R⁸, —CN, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′) and     —NR⁸C(O)R^(8′); -   X is alkyl, halo, haloalkyl, or haloalkoxy; -   R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo, nitro,     —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),     —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),     —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN),     —CH₂NR²⁵C(—NH)(R²⁵), —CH₂NR²⁵C(NR^(25a))(R^(25b))═CH(NO₂), alkyl,     alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where     the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and     heterocycloalkyl are independently optionally substituted with one,     two, three, four, five, six or seven groups independently selected     from halo, alkyl, haloalkyl, nitro, optionally substituted     cycloalkyl, optionally substituted heterocycloalkyl, optionally     substituted aryl, optionally substituted arylalkyl, optionally     substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN,     —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of     R¹ and R² together with the carbon to which they are attached, R³     and R⁴ together with the carbon to which they are attached, and R⁵     and R⁶ together with the carbon to which they are attached form C(O)     or C(═NOH); -   m is 0, 1, or 2; -   R⁷ is hydrogen, halo or alkyl; -   R⁸, R^(8′) and R^(8″) are independently selected from hydrogen,     hydroxy, optionally substituted alkoxy, alkyl, alkenyl, alkynyl,     aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; where the alkyl,     alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl     are independently optionally substituted with one, two three, four,     or five groups independently selected from alkyl, halo, hydroxy,     hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl,     carboxy, alkoxycarbonyl, alkenyloxycarbonyl, optionally substituted     cycloalkyl, optionally substituted cycloalkyloxycarbonyl, optionally     substituted aryl, optionally substituted aryloxy, optionally     substituted aryloxycarbonyl, optionally substituted arylalkyl,     optionally substituted arylalkyloxy, optionally substituted     arylalkyloxycarbonyl, nitro, cyano, optionally substituted     heterocycloalkyl, optionally substituted heteroaryl, —S(O)_(n)R³¹     (where n is 0, 1, or 2 and R³¹ is optionally substituted alkyl,     optionally substituted aryl, optionally substituted     heterocycloalkyl, or optionally substituted heteroaryl),     —NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or alkyl and R^(34a) is     alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl),     —SO₂NR³⁵R^(35a) (where R³⁵ is hydrogen or alkyl and R^(35a) is     alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl),     —NR³²C(O)R^(32a) (where R³² is hydrogen or alkyl and R^(32a) is     alkyl, alkenyl, alkoxy, or cycloalkyl), —NR³⁰R^(30′) (where R³⁰ and     R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl), and     —C(O)NR³³R^(33a) (where R³³ is hydrogen or alkyl and R^(33a) is     alkyl, alkenyl, alkynyl, or cycloalkyl); -   R⁹ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and     heterocycloalkyl; where the alkyl, alkenyl, alkynyl, aryl,     cycloalkyl, heteroaryl, and heterocycloalkyl are independently     optionally substituted with one, two, three, four, or five groups     selected from halo, hydroxy, alkyl, haloalkyl, haloalkoxy, amino,     alkylamino, and dialkylamino; -   R²⁵ and R^(25b) are independently hydrogen, alkyl, alkenyl,     optionally substituted cycloalkyl, or optionally substituted aryl;     and -   R^(25a) is hydrogen, alkyl, or alkenyl;     Group B: -   A is heteroarylene optionally substituted with one, two, three, or     four groups selected from R¹⁰, R¹², R¹⁴, R¹⁶ and R¹⁹ where R¹⁰, R¹²,     R¹⁴ and R¹⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,     halo, haloalkoxy, hydroxy, alkoxy, cyano, amino, alkylamino,     dialkylamino, haloalkyl, alkylsulfonylamino, alkylcarbonyl,     alkenylcarbonyl, alkoxycarbonyl, alkenyloxycarbonyl, aminocarbonyl,     alkylaminocarbonyl, dialkylaminocarbonyl, or alkylcarbonylamino;     where R¹⁹ is hydrogen, alkyl, or alkenyl; and where each alkyl and     alkenyl, either alone or as part of another group within R¹⁰, R¹²,     R¹⁴, R¹⁶, and R¹⁹ is independently optionally substituted with halo,     hydroxy, or alkoxy; -   X is alkyl, halo, haloalkyl, or haloalkoxy; -   R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo, nitro,     —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),     —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),     —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN),     —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,     alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where     the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and     heterocycloalkyl are independently optionally substituted with one,     two, three, four, five, six or seven groups independently selected     from halo, alkyl, haloalkyl, nitro, optionally substituted     cycloalkyl, optionally substituted heterocycloalkyl, optionally     substituted aryl, optionally substituted arylalkyl, optionally     substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN,     —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of     R¹ and R² together with the carbon to which they are attached, R³     and R⁴ together with the carbon to which they are attached, and R⁵     and R⁶ together with the carbon to which they are attached form C(O)     or C(═NOH); -   m is 1 or 2; -   R⁷ is hydrogen, halo or alkyl; and -   R⁸, R^(8′) and R^(8″) are independently selected from hydrogen,     hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl,     alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, where     the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and     heterocycloalkyl are independently optionally substituted with one,     two three, four, or five groups independently selected from alkyl,     halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy,     alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano,     —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ is optionally     substituted alkyl, optionally substituted aryl, optionally     substituted cycloalkyl, optionally substituted heterocycloalkyl, or     optionally substituted heteroaryl), —NR³⁶S(O)₂R^(36a) (where R³⁶ is     hydrogen, alkyl, or alkenyl and R^(36a) is alkyl, alkenyl,     optionally substituted aryl, optionally substituted cycloalkyl,     optionally substituted heterocycloalkyl, or optionally substituted     heteroaryl), —S(O)₂NR³⁷R^(37a) (where R³⁷ is hydrogen, alkyl, or     alkenyl and R^(37a) is alkyl, alkenyl, optionally substituted aryl,     optionally substituted cycloalkyl, optionally substituted     heterocycloalkyl, or optionally substituted heteroaryl), optionally     substituted cycloalkyl, optionally substituted heterocycloalkyl,     optionally substituted aryl, optionally substituted arylalkyl,     optionally substituted aryloxy, optionally substituted arylalkyloxy,     optionally substituted heteroaryl, —NHC(O)R³² (where R³² is alkyl,     alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′) (where R³⁰ and     R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl), and     —C(O)NHR³³ (where R³³ is alkyl, alkenyl, alkynyl, or cycloalkyl);     Group C: -   A is

-   where R¹⁰ is hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy,     hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkyl,     —NHS(O)₂R⁸, —CN, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′) and     —NR⁸C(O)R^(8′); -   R^(10a) is hydrogen, alkyl, or alkenyl; -   Y¹ is ═CH— or ═N—; -   X is alkyl, halo, haloalkyl, or haloalkoxy; -   R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo, nitro,     —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),     —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),     —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN),     —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(R^(25a)R^(25b))═CH(NO₂), alkyl,     alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where     the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and     heterocycloalkyl are independently optionally substituted with one,     two, three, four, five, six or seven groups independently selected     from halo, alkyl, haloalkyl, nitro, optionally substituted     cycloalkyl, optionally substituted heterocycloalkyl, optionally     substituted aryl, optionally substituted arylalkyl, optionally     substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN,     —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of     R¹ and R² together with the carbon to which they are attached, R³     and R⁴ together with the carbon to which they are attached, and R⁵     and R⁶ together with the carbon to which they are attached form C(O)     or C(═NOH); -   m is 1 or 2; -   R⁷ is hydrogen, halo or alkyl; and -   R⁸, R^(8′) and R^(8″) are independently selected from hydrogen,     hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl,     alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, where     the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and     heterocycloalkyl are independently optionally substituted with one,     two three, four, or five groups independently selected from alkyl,     halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy,     alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano,     —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ is optionally     substituted alkyl, optionally substituted aryl, optionally     substituted cycloalkyl, optionally substituted heterocycloalkyl, or     optionally substituted heteroaryl), —NR³⁶S(O)₂R^(36a) (where R³⁶ is     hydrogen, alkyl, or alkenyl and R^(36a) is alkyl, alkenyl,     optionally substituted aryl, optionally substituted cycloalkyl,     optionally substituted heterocycloalkyl, or optionally substituted     heteroaryl), —S(O)₂NR³⁷R^(37a) (where R³⁷ is hydrogen, alkyl, or     alkenyl and R^(37a) is alkyl, alkenyl, optionally substituted aryl,     optionally substituted cycloalkyl, optionally substituted     heterocycloalkyl, or optionally substituted heteroaryl), optionally     substituted cycloalkyl, optionally substituted heterocycloalkyl,     optionally substituted aryl, optionally substituted arylalkyl,     optionally substituted aryloxy, optionally substituted arylalkyloxy,     optionally substituted heteroaryl, —NHC(O)R³² (where R³² is alkyl,     alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R³⁰ (where R³⁰ and R^(30′)     are independently hydrogen, alkyl, or hydroxyalkyl), and —C(O)NHR³³     (where R³³ is alkyl, alkenyl, alkynyl, or cycloalkyl); or     Group D: -   A is

-   R⁴⁰ and R^(40a) are independently hydrogen or alkyl; -   X is alkyl, halo, haloalkyl, or haloalkoxy; -   R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo, nitro,     —NR⁸R^(8′), —R⁸R^(8′), —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,     —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),     —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN),     —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,     alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where     the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and     heterocycloalkyl are independently optionally substituted with one,     two, three, four, five, six or seven groups independently selected     from halo, alkyl, haloalkyl, nitro, optionally substituted     cycloalkyl, optionally substituted heterocycloalkyl, optionally     substituted aryl, optionally substituted arylalkyl, optionally     substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN,     —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of     R¹ and R² together with the carbon to which they are attached, R³     and R⁴ together with the carbon to which they are attached, and R⁵     and R⁶ together with the carbon to which they are attached form C(O)     or C(═NOH); -   m is 1 or 2; -   R⁷ is hydrogen, halo or alkyl; and -   R⁸, R^(8′) and R^(8″) are independently selected from hydrogen,     hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl,     alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, where     the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and     heterocycloalkyl are independently optionally substituted with one,     two three, four, or five groups independently selected from alkyl,     halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy,     alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano,     —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ is optionally     substituted alkyl, optionally substituted aryl, optionally     substituted cycloalkyl, optionally substituted heterocycloalkyl, or     optionally substituted heteroaryl), —NR³⁶S(O)₂R^(36a) (where R³⁶ is     hydrogen, alkyl, or alkenyl and R^(36a) is alkyl, alkenyl,     optionally substituted aryl, optionally substituted cycloalkyl,     optionally substituted heterocycloalkyl, or optionally substituted     heteroaryl), —S(O)₂NR³⁷R^(37a) (where R³⁷ is hydrogen, alkyl, or     alkenyl and R^(37a) is alkyl, alkenyl, optionally substituted aryl,     optionally substituted cycloalkyl, optionally substituted     heterocycloalkyl, or optionally substituted heteroaryl), optionally     substituted cycloalkyl, optionally substituted heterocycloalkyl,     optionally substituted aryl, optionally substituted arylalkyl,     optionally substituted aryloxy, optionally substituted arylalkyloxy,     optionally substituted heteroaryl, —NHC(O)R³² (where R³² is alkyl,     alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′) (where R³⁰ and     R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl), and     —C(O)NHR³³ (where R³³ is alkyl, alkenyl, alkynyl, or cycloalkyl).

DETAILED DESCRIPTION OF THE INVENTION Definitions for the Mek Compound

The following terms have the indicated meanings throughout:

The symbol “—” means a single bond, “═” means a double bond, “≡” means a triple bond, and

means a single bond and optionally a double bond. When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four.

When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four. For example, in the structure on the left-hand side of the schematic below there are nine hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a particular atom in a structure is described in textual formula as having a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, —CH₂CH₂—. It is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures.

If a group “R” is depicted as “floating” on a ring system, as for example in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as for example in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the —NH— in the formula above), implied hydrogen (for example as in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the formula above, “X” equals ═CH—) from one of the ring atoms, so long as a stable structure is formed. In the example depicted, the “R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula depicted above, when y is 2 for example, then the two “R's” may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.

When a group “R” is depicted as existing on a ring system containing saturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two “R's” may reside on the same carbon. A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an “annular” carbon). In another example, two R's on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring (a “spirocyclyl” group) structure with the depicted ring as for example in the formula:

“Acyl” means a —C(O)R radical where R is optionally substituted alkyl, optionally substituted alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, as defined herein, e.g., acetyl, benzoyl, trifluoromethylcarbonyl, or 2-methoxyethylcarbonyl, and the like.

“Acylamino” means a —NRR′ group where R is acyl, as defined herein, and R′ is hydrogen or alkyl.

“Administration” and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, and chemotherapy, etc.), “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.

“Alkenyl” means a means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one double bond, e.g., ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like.

“Alkenylcarbonyl” means a —C(O)R group where R is alkenyl, as defined herein.

“Alkenyloxycarbonyl” means a —C(O)OR group where R is alkenyl, as defined herein.

“Alkoxy” means an —OR group where R is alkyl group as defined herein. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like. Lower-alkoxy refers to groups containing one to six carbons.

“Alkoxyalkyl” means an alkyl group, as defined herein, substituted with at least one, preferably one, two, or three, alkoxy groups as defined herein. Representative examples include methoxymethyl and the like.

“Alkoxycarbonyl” means a —C(O)OR group where R is alkyl as defined herein.

“Alkoxycarbonylamino” means a —NR′R″ group where R′ is hydrogen, alkyl, hydroxy, or alkoxy and R″ is alkoxycarbonyl, as defined herein.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of one to eight carbon atoms or a branched saturated monovalent hydrocarbon radical of three to eight carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.

“Alkylamino” means a —NHR radical where R is alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, iso-butylamino, tert-butylamino, or methylamino-N-oxide, and the like.

“Alkylaminoalkyl” means an alkyl group substituted with one or two alkylamino groups, as defined herein.

“Alkylaminocarbonyl” means a —C(O)R group where R is alkylamino, as defined herein.

“Alkylcarbonyl” means a —C(O)R group where R is alkyl, as defined herein.

“Alkylcarbonylamino” means a —NRR′ group where R is hydrogen or alkyl as defined herein and R′ is alkylcarbonyl, as defined herein.

“Alkylcarbonyloxy” means an —OC(O)R group where R is alkyl, as defined herein.

“Alkylsulfonylamino” means a —NRS(O)₂R′ group where R is hydrogen or alkyl as defined herein, and R′ is alkyl, as defined herein.

“Alkynyl” means a straight or branched hydrocarbon radical having from 2 to 8 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.

“Aminoalkyl” means an alkyl group substituted with at least one amino group and in another embodiment, one, two or three amino groups.

“Aminocarbonyl” means a —C(O)NH₂ group.

“Aryl” means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, and indanyl, and the like.

“Arylene” means a divalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Representative examples include phenylene, naphthylene, and indanylene, and the like.

“Arylalkyl” means an alkyl group, as defined herein, substituted with one or two aryl groups, as defined herein. Examples include benzyl, phenethyl, and the like.

“Carboxy ester” means a —C(O)OR group where R is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which is defined herein. Representative examples include methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl, and the like.

“Cycloalkyl” means a monocyclic or fused bicyclic, saturated or partially unsaturated (but not aromatic), monovalent hydrocarbon radical of three to ten carbon ring atoms. Fused bicyclic hydrocarbon radical includes bridged ring systems. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. One or two ring carbon atoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. The term cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex-3-enyl, and the like.

“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,N-methylpropylamino or N,N-methylethylamino, and the like.

“Dialkylaminoalkyl” means an alkyl group substituted with one or two dialkylamino groups, as defined herein.

“Dialkylaminocarbonyl” means a —C(O)R group where R is dialkylamino, as defined herein.

“Fused-polycyclic” or “fused ring system” means a polycyclic ring system that contains fused rings and, unless otherwise indicated, can contain bridged rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic. In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to form a ring structure. The fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e. saturated ring structures) can contain two substitution groups.

“Haloalkoxy” means an —OR group where R′ is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

“Halogen” or “halo” means fluoro, chloro, bromo and iodo.

“Haloalkyl” means an alkyl group, as defined herein, that is substituted with one or more halogens, preferably one to five halo atoms. Representative examples include trifluoromethyl, difluoromethyl, 1-chloro-2-fluoro-ethyl, and the like.

“Heteroaryl” means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, preferably one, two, three, or four ring heteroatoms independently selected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N—, —N(R^(x))—, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. R^(x) is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, R^(x) is absent. The term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the derivatives thereof, or N-oxide or a protected derivative thereof.

“Heteroarylene” means a monocyclic, fused bicyclic, or fused tricyclic, divalent radical of 5 to 14 ring atoms containing one or more, preferably one, two, three, or four ring heteroatoms independently selected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N—, —N(R¹⁹)—, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. R¹⁹ is hydrogen, alkyl, or alkenyl. Unless stated otherwise, the valencies may be located on any atom of any ring of the heteroarylene group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, R^(x) is absent. The term heteroaryl includes, but is not limited to, thien-diyl, benzo[d]isoxazol-diyl, benzo[d]isothiazol-diyl, 1H-indazol-diyl (optionally substituted at the N1 position with R¹⁹), benzo[d]oxazol-diyl, benzo[d]thiazol-diyl, 1H-benzo[d]imidazol-diyl (optionally substituted at the N1 position with R¹⁹), 1H-benzo[d][1,2,3]triazol-diyl (optionally substituted at the N1 position with R¹⁹), imidazo[1,2-a]pyridin-diyl, cinnolin-diyl, quinolin-diyl, pyridin-diyl, 1-oxido-pyridin-diyl, [1,2,4]triazolo[4,3-a]pyridin-diyl, and 2,3-dihydroimidazo[1,2-a]pyridin-diyl, and the like.

“Heterocycloalkyl” means a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated (but not aromatic) monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more (and in another embodiment, one, two, three, or four) ring heteroatoms independently selected from O, S(O)_(n) (n is 0, 1, or 2), N, N(R^(y)) (where R^(y) is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. When the point of valency is located on a nitrogen atom, R^(y) is absent. The term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and the derivatives thereof and N-oxide or a protected derivative thereof.

“Hydroxyalkyl” means an alkyl, as defined herein, substituted with at least one, preferably one, two, or three, hydroxy group(s), provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl, and the like.

“Hydroxyamino” means a —NH(OH) group.

“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more optional substituents, only sterically practical and/or synthetically feasible compounds are meant to be included. “Optionally substituted” refers to all subsequent modifiers in a term. So, for example, in the term “optionally substituted arylC₁₋₈ alkyl,” both the “C₁₋₈ alkyl” portion and the “aryl” portion of the molecule may or may not be substituted. A list of exemplary optional substitutions is presented below in the definition of “substituted.”

“Optionally substituted alkoxy” means an —OR radical where R is optionally substituted alkyl as defined herein. Representative examples include —OCH₂CH₂OCH₃, —OCH₂CH₂OH, —OCH₂CH(NH₂)CH₃, and the like.

“Optionally substituted alkyl” means an alkyl radical, as defined herein, optionally substituted with one or more group(s) (and in another embodiment one, two, three, four, or five groups) independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, halo, hydroxy, hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy, —S(O)₀₋₂-alkyl, —S(O)₀₋₂-alkenyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, —NR^(c)S(O)₂-alkyl (where R^(c) is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and —C(O)NR^(a)R^(b) (where R^(a) and R^(b) are independently hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).

“Optionally substituted aryl” means an aryl group, as defined herein, which is optionally substituted with one, two, three, four, of five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, —C(O)NR′R″ (where R′ is hydrogen or alkyl and R″ is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ is alkyl, aryl, heteroaryl, or heterocycloalkyl), and —NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Optionally substituted arylalkyl means an alkyl group substituted with one or two optionally substituted aryl group(s) as defined herein.

“Optionally substituted arylalkyloxy” means an —OR group where R is optionally substituted arylalkyl, as defined herein.

“Optionally substituted arylalkyloxycarbonyl” means a —C(O)R group where R is optionally substituted arylalkyloxy, as defined herein.

“Optionally substituted aryloxy” means an —OR group where R is optionally substituted aryl, as defined herein.

“Optionally substituted aryloxycarbonyl” means a —C(O)R group where R is optionally substituted aryloxy as defined herein.

“Optionally substituted cycloalkyl” means a cycloalkyl radical, as defined herein, that is optionally substituted with one, two, three, or four groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, oxo, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, dialkylamino, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl dialkylaminoalkyl, carboxy, carboxy ester, cycloalkyl, hydroxyalkyl, —C(O)NR′R″ (where R′ is hydrogen, alkyl, hydroxy, or alkoxy and R″ is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), optionally substituted heterocycloalkyl, optionally substituted heteroaryl, —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ is alkyl, aryl, heteroaryl, or heterocycloalkyl), and —NHS(O)₂R′ (where R′ is alkyl, aryl, or heterocyclyl).

“Optionally substituted cycloalkyloxycarbonyl” means a —C(O)OR group where R is optionally substituted cycloalkyl as defined herein.

“Optionally substituted heteroaryl” means a heteroaryl group, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, oxo (valency rules permitting), carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, heteroaryl, optionally substituted aryl, —C(O)NR′R″ (where R′ is hydrogen or alkyl and R″ is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), —NR′C(O)R′ (where R′ is hydrogen or alkyl and R″ is alkyl, aryl, heteroaryl, or heterocycloalkyl), and —NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Optionally substituted heterocycloalkyl” means a heterocycloalkyl ring, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo, alkyl, alkenyl, alkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, —C(O)NR′R″ (where R′ is hydrogen or alkyl and R″ is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ is alkyl, aryl, heteroaryl, or heterocycloalkyl), amino, alkylamino, dialkylamino, and —NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Saturated bridged ring system” refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene, 7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class “saturated bridged ring system.”

“Spiro”, “Spirocyclyl” or “spiro ring” refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, a ring atom of a saturated bridged ring system (rings B and B′), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto.

“Yield” for each of the reactions described herein is expressed as a percentage of the theoretical yield.

Definitions for the Compound of Formula 100

The terms used to describe the scope of formula 100 are defined in WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004) which is herein incorporated by reference. For example “optionally substituted alkyl” for formula 100 has the meaning given in WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004). Whenever a compound of formula 100 is described in this application, whether by structure or by use of the term “formula 100,” the terms used to describe that compound are defined by WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004).

Definitions for the Compound of Formula 101

The terms used to describe the scope of formula 101 are defined in WO 2005/112932 (US Nat'l Stage application Ser. No. 11/568,789) which is herein incorporated by reference. For example “optionally substituted heterocyclyl” for formula 101 has the meaning given in WO 2005/112932 (US Nat'l Stage application Ser. No. 11/568,789). Whenever a compound of formula 101 is described in this application, whether by structure or by use of the term “formula 101,” the terms used to describe that compound are defined by WO 2005/112932 (US Nat'l Stage application Ser. No. 11/568,789).

Definitions for the Compound of Formula A-B-C

The terms used to describe the scope of formula A-B-C are defined in WO 2005/030140 (US Nat'l Stage application Ser. No. 10/573,336) which is herein incorporated by reference. For example “optionally substituted heterocyclyl” for formula A-B-C has the meaning given in WO 2005/030140 (US Nat'l Stage application Ser. No. 10/573,336). Whenever a compound of formula A-B-C is described in this application, whether by structure or by use of the term “formula A-B-C,” the terms used to describe that compound are defined by WO 2005/030140 (US Nat'l Stage application Ser. No. 10/573,336).

Definitions for the Compound of Formula 103

The terms used to describe the scope of formula 103 are defined in WO 2006/014325 (US Nat'l Stage application Ser. No. 11/571,140) which is herein incorporated by reference. For example “optionally substituted heterocyclyl” for formula 103 has the meaning given in WO 2006/014325 (US Nat'l Stage application Ser. No. 11/571,140). Whenever a compound of formula 103 is described in this application, whether by structure or by use of the term “formula 103,” the terms used to describe that compound are defined by WO 2006/014325 (US Nat'l Stage application Ser. No. 11/571,140).

Definitions for the Compound of Formula 105

The terms used to describe the scope of formula 105 are defined in WO 2006/074057 (US Nat'l Stage application Ser. No. 11/722,719) which is herein incorporated by reference. For example “optionally substituted heterocyclyl” for formula 105 has the meaning given in WO 2006/074057 (US Nat'l Stage application Ser. No. 11/722,719). Whenever a compound of formula 105 is described in this application, whether by structure or by use of the term “formula 105,” the terms used to describe that compound are defined by WO 2006/074057 (US Nat'l Stage application Ser. No. 11/722,719).

Definitions for the Compound of Formula 107

The terms used to describe the scope of formula 107 are defined in WO 2004/050681 (US Nat'l Stage application Ser. No. 10/533,555) which is herein incorporated by reference. For example “optionally substituted aryl” for formula 107 has the meaning given in WO 2004/050681 (US Nat'l Stage application Ser. No. 10/533,555). Whenever a compound of formula 107 is described in this application, whether by structure or by use of the term “formula 107,” the terms used to describe that compound are defined by WO 2004/050681 (US Nat'l Stage application Ser. No. 10/533,555).

Definitions for the Compound of Formula 108

The terms used to describe the scope of formula 108 are defined in WO 2005/117909 (US Nat'l Stage application Ser. No. 11/568,173) which is herein incorporated by reference. For example “optionally substituted aryl” for formula 108 has the meaning given in WO 2005/117909 (US Nat'l Stage application Ser. No. 11/568,173). Whenever a compound of formula 108 is described in this application, whether by structure or by use of the term “formula 108,” the terms used to describe that compound are defined by WO 2005/117909 (US Nat'l Stage application Ser. No. 11/568,173).

Definitions for the Compound of Formula 109

The terms used to describe the scope of formula 109 are defined in WO 2006/071819 (US Nat'l Stage application Ser. No. 11/722,291 which is herein incorporated by reference. For example “optionally substituted aryl” for formula 109 has the meaning given in WO 2006/071819 (US Nat'l Stage application Ser. No. 11/722,291. Whenever a compound of formula 109 is described in this application, whether by structure or by use of the term “formula 109,” the terms used to describe that compound are defined by WO 2006/071819 (US Nat'l Stage application Ser. No. 11/722,291.

Other Definitions

“AKT inhibitor” includes, for example, LY294002, PKC412, and compounds described in WO 2006/071819 and WO05/117909.

“Alkylating agent(s)” includes, for example, one or more of the following: Chlorambucil, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan, Carmustine, Streptozocin, Fotemustine, Lomustine, Streptozocin, Carboplatin, Cisplatin, Oxaliplatin, BBR3464, Busulfan, Dacarbazine, Mechlorethamine, Procarbazine, Temozolomide, ThioTEPA, and Uramustine.

“Antibody(s)” includes, for example, one or more of the following: IGF1R antibody (including, for example, ^(α)IGF-1R A12 MoAb, 19D12, h7C10 and CP-751871), Alemtuzumab, Bevacizumab (Avastin®), Cetuximab (Erbitux®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab (tiuxetan), Panitumumab, Rituximab, Tositumomab, and Trastuzumab (Herceptin®).

“Antimetabolite(s)” include, for example, methotrexate, Pemetrexed, Raltitrexed, Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Thioguanine, Capecitabine, Cytarabine, fluorouracil (administered with or without leucovorin or folinic acid), and Gemcitabine.

“Antimicrotubule agent(s)” includes, for example, Vincristine, Vinblastine, Vinorelbine, Vinflunine, and Vindesine.

“Aromatase inhibitor(s)” includes, for example, one or more of the following: Aminoglutethimide, Anastrozole (Arimidex®), Letrozole (Femara®), Exemestane (Aromasin®), and Formestane (Lentaron®).

“Cancer” refers to cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinorna, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformians), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastorna multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; Adrenal Glands: neuroblastoma; and breast cancer. Thus, the term “cancerous cell” as provided herein, includes a cell afflicted by any one of the above-identified conditions.

“cMET inhibitor” includes, for example, compounds described in WO06/108059, WO 2006/014325, and WO 2005/030140.

“EGFR inhibitor” includes, for example, one or more of the following: Lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), AEE788 and HKI-272, EKB-569, CI1033, and compounds described in WO 2004/006846 and WO 2004/050681.

“ErbB2 inhibitor” includes, for example, Lapatinib (GW572016), and PKI-166.

“Hormone therapy” or “hormonal therapy” includes, for example, treatment with one or more of the following: steroids (e.g. dexamethasone), finasteride, tamoxifen, and an aromatase inhibitor.

“HSP90 inhibitor(s)” includes, for example, 17-AAG, 17-DMAG, Geldanamycin, 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide [NVP-AUY922 (VER52296)], 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-2-amine (CNF2024, also named BIIB021), compounds disclosed in WO2004072051 (which is herein incorporated by reference), compounds disclosed in WO2005028434 (which is herein incorporated by reference), compounds disclosed in WO2007035620 (which is herein incorporated by reference) and compounds disclosed in WO2006091963 (which is herein incorporated by reference).

“Hypothermia therapy” is a type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs.

“IGF1R inhibitor(s)” include, for example, Tyrphostin AG 1024 and compounds described in WO06/074057.

“Kinase-dependent diseases or conditions” refer to pathologic conditions that depend on the activity of one or more protein kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).

While not wishing to be bound to theory, phosphatases can also play a role in “kinase-dependent diseases or conditions” as cognates of kinases; that is, kinases phosphorylate and phosphatases dephosphorylate, for example protein substrates. Therefore compounds of the invention, while modulating kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic (or not) to activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family. In any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth.

“Metabolite” refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.

“Patient” for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In an embodiment the patient is a mammal, and in another embodiment the patient is human.

A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17^(th) ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference or S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19 both of which are incorporated herein by reference.

Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid and the like.

Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

“Platin(s),” and “platin-containing agent(s)” include, for example, cisplatin, carboplatin, and oxaliplatin.

“Prodrug” refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

“Raf inhibitor(s)” include, for example, sorafenib and compounds described in WO 2005/112932.

“Rapamycin analogue(s)” include for example, CCI-779, AP23573, RAD001, TAFA93, and compounds described in WO 2004/101583 and U.S. Pat. No. 7,160,867 which are each incorporated herein by reference in their entireties.

“Receptor Tyrosine Kinase inhibitor(s)” includes, for example, inhibitors of AKT, EGFR, ErbB2, IGF1R, Met, Raf, and VEGFR2. Examples of receptor tyrosine kinase inhibitors can be found in WO 2006/108059 (US Nat'l Stage application Ser. No. 11/910,720), WO 2006/074057 (US Nat'l Stage Application Ser. No. 11/722,719), WO 2006/071819 (US Nat'l Stage application Ser. No. 11/722,291), WO 2006/014325 (US Nat'l Stage application Ser. No. 11/571,140), WO 2005/117909 (US Nat'l Stage application Ser. No. 11/568,173), WO 2005/030140 (US Nat'l Stage application Ser. No. 10/573,336), WO 2004/050681 US Nat'l Stage application Ser. No. 10/533,555), WO 2005/112932 (US Nat'l Stage application Ser. No. 11/568,789), and WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004), each of which is incorporated herein by reference for all purposes. In particular, the applications cited in this paragraph are incorporated for the purpose of providing specific examples and generic embodiments (and the definitions associated with the terms used in the embodiments) of compounds that are useful in the practice of the invention. These references also describe in vitro assays useful in the practice of this invention.

“Taxane(s)” includes, for example, one or more of the following: Paclitaxel (Taxol®) and Docetaxel (Taxotere®).

“Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease. The amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.

“Topoisomerase inhibitor” includes, for example, one or more of the following: amsacrine, camptothecin, etoposide, etoposide phosphate, exatecan, irinotecan, lurtotecan, and teniposide, and topotecan.

“Treating” or “treatment” of a disease, disorder, or syndrome, as used herein, includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.

“SRC and/or ABL kinase inhibitor(s)” includes, for example, dasatinib, imatinib (Gleevec®), and compounds described in WO 2006/074057.

“VEGFR inhibitor” includes, for example, one or more of the following: ZD6474 (Zactima), sorafenib, Angiozyme, AZD2171, SU5416, PTK787, AEE788, sunitinib (SUTENT), and compounds described in WO 2004/050681 and WO 2004/006846.

Embodiments Of The Invention

In one embodiment, the cancer is mediated, at least in part, by inhibiting MEK.

In another embodiment, the cancer is selected from melanoma, colon cancer, rectal cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, papillary thyroid cancer, anaplastic thyroid cancer, endometrial cancer, and ovarian cancer.

In another embodiment, one or more of the treatment(s) is one or more chemotherapeutic agent(s).

In another embodiment, one or more of the chemotherapeutic agent(s) is selected from a taxane(s), a platin(s), a topoisomerase inhibitor(s), an alkylating agent(s), an antimetabolite(s), an antimicrotubule agent(s), and a bcr-abl inhibitor(s).

In another embodiment, one or more of the chemotherapeutic agent(s) is an antimicrotubule agent(s) selected from Vincristine, Vinblastine, Vinorelbine, and Vindesine.

In another embodiment, one or more of the chemotherapeutic agent(s) is selected from rapamycin, carboplatin, cisplatin, oxaliplatin, gemcitabine, dacarbazine, topotecan, and irinotecan.

In another embodiment, one or more of the chemotherapeutic agent(s) is an AKT inhibitor. In another embodiment, the AKT inhibitor is selected from a compound in Table 2a and Table 2b.

In another embodiment, one or more of the chemotherapeutic agent(s) is selected from a compound in Table 2a and Table 2b.

In another embodiment, one or more of the chemotherapeutic agent(s) is a cMET inhibitor. In another embodiment, the cMET inhibitor is selected from a compound in Table 3a, Table 3b, and Table 3c.

In another embodiment, one or more of the chemotherapeutic agent(s) is selected from a compound in Table 3a, Table 3b, and Table 3c.

In another embodiment, one or more of the chemotherapeutic agent(s) is an EGFR inhibitor. In another embodiment, the EGFR inhibitor is selected from Lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), AEE788, HKI-272, EKB-569, CI1033, and a compound selected from Table 4 and Table 7. In another embodiment, the EGFR inhibitor is selected from Table 4 and Table 7.

In another embodiment, one or more of the chemotherapeutic agent(s) is a compound selected from Table 4 and Table 7.

In another embodiment, one or more of the chemotherapeutic agent(s) is an ErbB2 inhibitor. In another embodiment, the chemotherapeutic agent(s) is selected from lapatinib, EKB-569, HK1272, and CI1033.

In another embodiment, one or more of the chemotherapeutic agent(s) is an HSP90 inhibitor. In another embodiment, the HSP90 inhibitor is 17-AAG, 17-DMAG, Geldanamycin, and CNF2024.

In another embodiment, one or more of the chemotherapeutic agent(s) is an IGF1R inhibitor. In another embodiment, the IGF1R inhibitor is selected from a compound in Table 5a and Table 5b.

In another embodiment, one or more of the chemotherapeutic agent(s) is selected from a compound in Table 5a and Table 5b.

In another embodiment, one or more of the chemotherapeutic agent(s) is an Raf inhibitor. In another embodiment, the Raf inhibitor is selected from sorafenib and a compound in Table 6.

In another embodiment, one or more of the chemotherapeutic agent(s) is a VEGFR inhibitor. In another embodiment, the VEGFR inhibitor is selected from a compound in Table 4 and Table 7.

In another embodiment, one or more of the chemotherapeutic agent(s) is selected from rapamycin, a rapamycin analogue, PI103, SF1126, and BEZ235. In another embodiment, one or more of the chemotherapeutic agent(s) is selected from rapamycin, CCI-779, AP23573, RAD001, TAFA93, PI103, SF1126, and BEZ235. In another embodiment, one or more of the chemotherapeutic agent(s) is selected from rapamycin, CCI-779, AP23573, RAD001, PI103, and SF1126. In another embodiment, one or more of the chemotherapeutic agent(s) is rapamycin. In another embodiment, one or more of the chemotherapeutic agent(s) is a rapamycin analogue.

In another embodiment, one or more of the chemotherapeutic agent(s) is 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile.

In another embodiment, one or more of the treatment(s) is selected from radiation and hypothermia therapy. In another embodiment, one or more of the treatment(s) is radiation.

In another embodiment, one or more of the treatment(s) is one or more antibody(s). In another embodiment, one or more of the antibody(s) is selected from IGF1R antibody (including, for example, ^(α)IGF-1R A12 MoAb, 19D12, h7C10 and CP-751871), Alemtuzumab, Bevacizumab (Avastin®), Cetuximab (Erbitux®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab (tiuxetan), Panitumumab, Rituximab, Tositumomab, and Trastuzumab (Herceptin®).

In another embodiment, one or more of the treatment(s) is surgery.

In another embodiment, one or more of the treatment(s) is one or more hormone therapy(s). In another embodiment, one or more of the hormone therapy(s) is selected from tamoxifen and an aromatase inhibitor.

In another embodiment, one or more of the chemotherapeutic agent(s) is gemcitabine.

In another embodiment, one or more of the chemotherapeutic agent(s) is Imatinib (i.e. Gleevec®).

In another embodiment, the cancer is primary or relapsed CML and/or acute myelogenous leukemia (AML) and one or more of the treatment(s) is selected from one or more of the chemotherapeutic agent(s) and one or more antibody(s). In another embodiment one or more of the chemotherapeutic agent(s) is selected from Imatinib (i.e. Gleevec®) and PKC412; in another embodiment, one or more of the chemotherapeutic agent(s) is Imatinib (i.e. Gleevec®). In another embodiment one or more of the antibody(s) is selected from ^(α)IGF-1R A12 MoAb and trastuzumab.

In another embodiment, the cancer is prostate cancer and one or more of the treatment(s) is selected from one or more antibody(s). In another embodiment one or more of the antibody(s) is ^(α)IGF-1R A12 MoAb.

In another embodiment, the cancer is malignant melanoma and one or more of the treatment(s) is selected from surgery and one or more chemotherapeutic agent(s). In another embodiment, one or more of the chemotherapeutic agent(s) is selected from an alkylating agent(s), a taxane(s), a platin(s), and a Raf inhibitor(s). In another embodiment, one or more chemotherapeutic agent(s) is selected from sorafenib, Paclitaxel (Taxol®), Docetaxel (Taxotere®), dacarbazine, rapamycin, imatinib mesylate (Gleevec®), sorafenib, and carboplatin.

In another embodiment, the cancer is colon or rectal cancer and one or more of the treatment(s) is selected from surgery, radiation, one or more chemotherapeutic agent(s), and one or more antibody(s). In another embodiment, one or more of the chemotherapeutic agent(s) is selected from cisplatin, oxaliplatin, carboplatin, 5-fluorouracil, Capecitabine (Xeloda), Irinotecan (Camptosar), FOLFOX (Folinic acid, 5-FU, Oxaliplatin), and leucovorin. In another embodiment one or more of the antibody(s) is selected from bevacizumab and cetuximab.

In another embodiment, the cancer is pancreatic cancer and one or more of the treatment(s) is selected from surgery, radiation, and one or more chemotherapeutic agent(s). In another embodiment, one or more of the chemotherapeutic agent(s) is selected from erlotinib (Tarceva®), gemcitabine, 5-fluorouracil, leucovorin, cisplatin, oxaliplatin, carboplatin, gemcitabine, irinotecan, paclitaxel, capecitabine, and streptozocin.

In another embodiment, the cancer is breast cancer and one or more of the treatment(s) is selected from surgery, radiation, one or more chemotherapeutic agent(s), one or more hormone therapy(s), and one or more antibody(s). In another embodiment one or more of the chemotherapeutic agent(s) is selected from lapatinib (Tykerb®), Paclitaxel (Taxol®), docetaxel, capecitabine, Cyclophosphamide (Cytoxan), methotrexate, fluorouracil, doxorubicin, epirubicin, gemcitabine, carboplatin (Paraplatin), cisplatin (Platinol), vinorelbine (Navelbine), capecitabine (Xeloda), pegylated liposomal doxorubicin (Doxil), and albumin-bound paclitaxel (Abraxane). In another embodiment one or more of the antibody(s) is selected from ^(α)IGF-1R A12 MoAb, bevacizumab (Avastin), and trastuzumab. In another embodiment, one or more of the hormone therapy(s) is selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, and an aromatase inhibitor(s); in another embodiment, one or more of the aromatase inhibitor(s) is selected from etrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin).

In another embodiment, the cancer is non-small cell lung cancer and one or more of the treatment(s) is selected from surgery, radiation, one or more antibody(s), and one or more chemotherapeutic agent(s). In another embodiment, the chemotherapeutic agent(s) is selected from cisplatin, oxaliplatin, carboplatin, Zactima (ZD6474), Paclitaxel, Docetaxel (Taxotere®), Gemcitabine (Gemzar®), Vinorelbine, Irinotecan, Etoposide, Vinblastine, Erlotinib (Tarceva®), and Pemetrexed. In another embodiment, one or more of the antibody(s) is Bevacizumab.

In another embodiment, the cancer is small cell lung cancer and one or more of the treatment(s) is selected from surgery, radiation, and one or more chemotherapy agent(s). In another embodiment, one or more of the chemotherapy agent(s) is selected from cisplatin, oxaliplatin, carboplatin, etoposide, irinotecan, fosfamide, paclitaxel, docetaxel, gemcitabine, Topotecan, cyclophosphamide/doxorubicin/vincristine (CAV), methotrexate, and vinorelbine.

In another embodiment, the cancer is papillary or anaplastic thyroid cancer, and one or more of the treatment(s) is selected from surgery, radiation, radioactive iodine therapy, one or more hormone therapy(s), and one or more chemotherapeutic agent(s). In another embodiment, one or more of the chemotherapeutic agent(s) is selected from thyroid hormone pills, Doxorubucin and a platin(s).

In another embodiment, the cancer is endometrial cancer and one or more of the treatment(s) is selected from surgery, radiation, hormone therapy, and one or more chemotherapeutic agent(s). In another embodiment, one or more of the chemotherapeutic agent(s) is selected from paclitaxel, doxorubicin, and cisplatin. In another embodiment, one or more of the hormone therapy is selected from medroxyprogesterone acetate, megestrol acetate, and Tamoxifen.

In another embodiment, the cancer is ovarian cancer and one or more of the treatment(s) is selected from surgery, radiation, and one or more chemotherapeutic agent(s). In another embodiment, one or more of the chemotherapeutic agent(s) is selected from a platin(s) compound (such as cisplatin, oxaliplatin and carboplatin), a taxane (such as paclitaxel or docetaxel), topotecan, anthracyclines (such as doxorubicin (Adriamycin) and liposomal doxorubicin (Doxil)), gemcitabine, cyclophosphamide, vinorelbine (Navelbine), hexamethylmelamine, ifosfamide, and etoposide.

In another embodiment, one or more of the treatment(s) is selected from one or more chemotherapeutic agent(s), radiation, hypothermia therapy, one or more antibody(s), and surgery. In another embodiment, one or more of the chemotherapeutic agent(s) is selected from an EGFR inhibitor, isotretinoin, a platin (e.g., cisplatin, oxaliplatin, and carboplatin), epirubicin, bleomycin, doxorubicin, cyclophosphamide, a taxane (e.g. docetaxel (Taxotere®)), and fluorouracil [5-FU]. In another embodiment, one or more of the chemotherapeutic agent(s) is selected from cisplatin, carboplatin, and docetaxel. In another embodiment, one or more of the antibody(s) is cetuximab (Erbitux®).

In another embodiment one or more of the treatment(s) is selected from radiation and surgery.

In another embodiment of the invention, one or more of the treatments is selected from rapamycin, CCI-779, AP23573, RAD001, carboplatin, cisplatin, oxaliplatin, gemcitabine, dacarbazine, topotecan, irinotecan, sorafenib, paclitaxel, docetaxel, Lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), 5-fluorouracil, Capecitabine (Xeloda), FOLFOX (Folinic acid, 5-FU, Oxaliplatin), streptozocin, Cyclophosphamide (Cytoxan), methotrexate, doxorubicin, epirubicin, vinorelbine (Navelbine), pegylated liposomal doxorubicin (Doxil), and albumin-bound paclitaxel (Abraxane), Etoposide, Vinblastine, Pemetrexed, leucovorin, fosfamide, cyclophosphamide/doxorubicin/vincristine (CAV), thyroid hormone pills, hexamethylmelamine, ifosfamide, Imatinib (i.e. Gleevec®), ^(α)IGF-1R A12 MoAb, IGF-1R 19D12, IGF-1R h7C10, IGF-1R CP-751871, Alemtuzumab, Bevacizumab (Avastin®), Cetuximab (Erbitux®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab (tiuxetan), Panitumumab, Rituximab, Tositumomab, Trastuzumab (Herceptin®), tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, medroxyprogesterone acetate, megestrol acetate, and an aromatase inhibitor.

In another embodiment, one or more of the chemotherapeutic agent(s) is of formula 100:

where q is 1, 2, or 3; E is —NR⁹—, —O—, or absent and Y is —CH₂CH₂—, —CH₂—, or absent provided that when E is —NR⁹— or —O—, then Y is —CH₂CH₂—; R² is selected from halogen, trihalomethyl, —CN, —NO₂, —OR³, and optionally substituted lower alkyl; R⁸ is selected from —H, optionally substituted lower alkyl, —CO₂R³, —C(O)N(R³)R⁴, —SO₂R⁴, and —C(O)R³; or a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt or hydrate thereof. The terms used to describe the scope of formula 100 are defined in WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004) which is herein incorporated by reference. For example “optionally substituted alkyl” for formula 100 has the meaning given in WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004). Whenever a compound of formula 100 is described in this application, whether by structure or by use of the term “formula 100,” the terms used to describe that compound are defined by WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004).

In another embodiment, one or more of the chemotherapeutic agent(s) is of formula 101:

or a pharmaceutically acceptable salt, hydrate or solvate thereof, where

-   A is a three- to seven-membered alicyclic, a five- to six-membered     ortho-arylene or a five- to six-membered ortho-heteroarylene     containing between one and three heteroatoms, either of the     aforementioned optionally substituted with up to four R; -   each R is independently selected from —H, halogen, —CN, —NO₂, —OR³,     —N(R³)R³, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³,     —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, —OC(O)R³,     optionally substituted C₁₋₆alkyl, optionally substituted aryl,     optionally substituted aryl C₁₋₆alkyl, optionally substituted     heterocyclyl, and optionally substituted heterocyclyl C₁₋₆alkyl; -   optionally two of R, together with the atoms to which they are     attached, form a first ring system fused with A, said first ring     system substituted with zero to three of R¹; -   X₁, X₂ and X₃ are independently selected from —CR¹═ or —N═; -   each R¹ is independently selected from —H, halogen, —CN, —NO₂, —OR³,     —N(R³)R³, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³,     —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, —OC(O)R³,     optionally substituted C₁₋₆alkyl, optionally substituted aryl,     optionally substituted aryl C₁₋₆alkyl, optionally substituted     heterocyclyl, and optionally substituted heterocyclyl C₁₋₆alkyl; -   Z and X are each independently selected from —C(R²)═, —N═, —N(R²)—,     —S(O)₀₋₂—, and —O—; -   E and Y are each independently selected from absent, —C(R²)(R²)—,     —C(═O)—, —C(R²)═ and —N═, but E and Y are not both absent, and E and     Y are not both —N═ when both Z and X are —N═; -   each R² is independently selected from R³, —N(R³)(R³), —C(O)N(R³)R³,     —N(R³)CO₂R³, —N(R³)C(O)N(R³)R³, and —N(R³)C(O)R³; -   each R³ is independently selected from —H, optionally substituted     C₁₋₆alkyl, optionally substituted C₃₋₇alicyclic, optionally     substituted aryl, optionally substituted aryl C₁₋₃alkyl, optionally     substituted heterocyclyl, and optionally substituted heterocyclyl     C₁₋₃alkyl; -   optionally two of R³, when taken together with a common nitrogen to     which they are attached, form an optionally substituted five- to     seven-membered heterocyclyl, said optionally substituted five- to     seven-membered heterocyclyl optionally containing at least one     additional heteroatom selected from N, O, S, and P; and -   G is selected from —CO₂R³, —C(O)R³, —C(O)N(R³)R³, —C(O)(R³),     —C(O)NR³[C(R³)₂]₀₋₁R³, —C(O)NR³O[C(R³)₂]₀₋₁R³, —N(R³)CO₂R³,     —N(R³)C(O)N(R³)R³, —N(R³)C(O)R³, —N(R³)R³, —S(O)₀₋₂R³, —SO₂N(R³)R³,     optionally substituted aryl C₀₋₃alkyl, and optionally substituted     heterocyclyl C₀₋₃alkyl; -   with the proviso, however, that the compound is not     2-[(3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl)carbonyl]-N-(2-furanylmethyl)-benzamide,     N-cyclopropyl-2-[(3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl)carbonyl]-benzamide,     or     2-[(3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl)carbonyl]-N-(phenylmethyl)-benzamide.     The terms used to describe the scope of formula 101 are defined in     WO 2005/112932 (US Nat'l Stage application Ser. No. 11/568,789)     which is herein incorporated by reference. For example “optionally     substituted heterocyclyl” for formula 101 has the meaning given in     WO 2005/112932 (US Nat'l Stage application Ser. No. 11/568,789).     Whenever a compound of formula 101 is described in this application,     whether by structure or by use of the term “formula 101,” the terms     used to describe that compound are defined by WO 2005/112932 (US     Nat'l Stage application Ser. No. 11/568,789).

In another embodiment, one or more of the chemotherapeutic agent(s) is of formula A-B-C or a pharmaceutically acceptable salt or hydrate thereof, wherein, A is selected from:

B is selected from:

and, C is selected from:

-   wherein R² is selected from —H, halogen, trihalomethyl, —CN, —NH₂,     —NO₂, —OR³, —NR³R³, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,     —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionally     substituted lower alkyl; -   q is 0 to 2; -   each R³ is independently selected from —H, optionally substituted     lower alkyl, optionally substituted aryl, optionally substituted     arylalkyl, and optionally substituted heteroarylalkyl; -   two R³, together with the nitrogen to which they are attached, form     a four- to seven-membered heteroalicyclic, said four- to     seven-membered heteroalicyclic optionally containing one additional     heteroatom; when one said additional heteroatom is a nitrogen, then     said nitrogen is optionally substituted with a group selected from     —H, trihalomethyl, —SO₂R⁵, —SO₂NR⁵R⁵, —CO₂R⁵, —C(O)NR⁵R⁵, —C(O)R⁵,     and optionally substituted lower alkyl; -   each R³⁵ is independently selected from —H, —C(═O)R³, —C(═O)OR³,     —C(═O)SR³, —SO₂R³, —C(═O)N(R³)R³, and optionally substituted lower     alkyl; -   two R³⁵, together with the nitrogen to which they are attached, can     combine to form a heteroalicyclic optionally substituted with     between one and four of R⁶⁰, said heteroalicyclic may have an     additional annular heteroatom, and said heteroalicyclic may have an     aryl fused thereto, said aryl optionally substituted with an     additional one to four of R⁶⁰; -   A¹ is selected from ═N—, ═C(H)—, and ═C(CN)—; -   A² is either ═N— or ═C(H)—; -   R⁵ is —H or optionally substituted lower alkyl; -   R⁸ is selected from R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —SO₂R³, and     —C(O)R³; -   R⁹, R¹⁰, and R¹¹ are each independently selected from —H, and —OR¹²;     or -   R⁹ is selected from —H, and —OR¹², and R¹⁰ and R¹¹, when taken     together, are either an optionally substituted alkylidene or an oxo;     and -   R¹² is selected from —H, —C(O)R³, optionally substituted lower     alkylidyne, optionally substituted lower arylalkylidyne, optionally     substituted lower heterocyclylalkylidyne, optionally substituted     lower alkylidene, optionally substituted lower alkylidenearyl,     optionally substituted lower alkylideneheterocyclyl, optionally     substituted lower alkyl, optionally substituted lower alkylaryl,     optionally substituted aryl, optionally substituted lower     heterocyclylalkyl, and optionally substituted heterocyclyl; -   or two R¹²'s, when taken together, form 1) a corresponding     spirocyclic ketal when said two R¹²'s stem from R¹⁰ and R¹¹, or 2) a     corresponding cyclic ketal when said two R¹²'s stem from R⁹ and one     of R¹⁰ and R¹¹; -   E¹ is selected from —O—, —CH₂—, —N(R⁵)—, and —S(O)₀₋₂—; -   Q is a five- to ten-membered ring system, optionally substituted     with between zero and four of R²⁰; -   R²⁰ is selected from —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂,     —OR³, —NR³R³, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,     —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionally     substituted lower alkyl; -   R⁶⁰ is selected from —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂,     —OR³, —NR³R³, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,     —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally     substituted lower alkyl, optionally substituted aryl, optionally     substituted heteroarylalkyl, and optionally substituted arylalkyl; -   two of R⁶⁰, when attached to a non-aromatic carbon, can be oxo; -   each methylene in any of the above formulae is independently     optionally substituted with R²⁵; -   each R²⁵ is independently selected from halogen, trihalomethyl, —CN,     —NO₂, —NH₂, —OR³, —NR³R³, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,     —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally     substituted aryl, optionally substituted arylalkyl, heteroarylalkyl,     and optionally substituted lower alkyl; two of R²⁵, together with     the carbon or carbons to which they are attached, can combine to     form a three- to seven-membered alicyclic or heteroalicyclic, two of     R²⁵ on a single carbon can be oxo; -   with the proviso that when B is selected from:

and C contains

and the remaining portion of C contains one of:

directly attached to

then A must be one of:

and with the proviso that when C contains

and B is selected from:

then the portion of C directly attached to

cannot contain

when R⁷⁰ is selected from —H, C₁₋₄alkyl, and C₁₋₄alkoxyl. The terms used to describe the scope of formula A-B-C are defined in WO 2005/030140 (US Nat'l Stage application Ser. No. 10/573,336) which is herein incorporated by reference. For example “optionally substituted heterocyclyl” for formula A-B-C has the meaning given in WO 2005/030140 (US Nat'l Stage application Ser. No. 10/573,336). Whenever a compound of formula A-B-C is described in this application, whether by structure or by use of the term “formula A-B-C,” the terms used to describe that compound are defined by WO 2005/030140 (US Nat'l Stage application Ser. No. 10/573,336).

In another embodiment, one or more of the chemotherapeutic agent(s) is of formula 103:

or a pharmaceutically acceptable salt or hydrate hereof, wherein,

-   each of J¹, J², and J³ is independently selected from ═N—, ═C(R¹)—,     —N(R¹)—, —O— and —S(O)₀₋₂—; -   each R¹ is independently selected from —H, halogen, trihalomethyl,     —CN, —NO₂, —OR²⁰, —N(R²⁰)R²⁰, —S(O)₀₋₂R²⁰, —SO₂N(R²⁰)R²⁰, —CO₂R²⁰,     —C(O)N(R²⁰)R²⁰, —N(R²⁰)SO₂R²⁰, —N(R²⁰)C(O)R²⁰, —NCO₂R²⁰, —C(O)R²⁰,     optionally substituted C₁₋₆alkyl, optionally substituted aryl,     optionally substituted aryl C₁₋₆alkyl, optionally substituted     heterocyclyl, optionally substituted heterocyclyl C₁₋₆alkyl and     -D-R⁵⁰; -   R² is selected from —H, halogen, —OR²⁰, —S(O)₀₋₂R²⁰, —NO₂,     —N(R²⁰)R²⁰, and optionally substituted C₁₋₆alkyl; -   J⁴ is selected from ═N—, ═C(H)—, and ═C(CN)—; -   Ar is either a five- or six-membered arylene or a five- or     six-membered heteroarylene containing between one and three     heteroatoms; -   each R³ is independently selected from —H, halogen, trihalomethyl,     —CN, —NO₂, —OR²⁰, —N(R²⁰)R²⁰, —S(O)₀₋₂R²⁰, —SO₂N(R²⁰)R²⁰, —CO₂R²⁰,     —C(O)N(R²⁰)R²⁰, —N(R²⁰)SO₂R²⁰, —N(R²⁰)C(O)R²⁰, —NCO₂R²⁰, —C(O)R²⁰,     optionally substituted C₁₋₆alkyl, optionally substituted aryl,     optionally substituted aryl C₁₋₆alkyl, optionally substituted     heterocyclyl, optionally substituted heterocyclyl C₁₋₆alkyl and a     group —B-L-T, wherein -   B is selected from absent, —N(R¹³)—, —N(SO₂R¹³)—, —O—, —S(O)₀₋₂—,     and —C(═O)—; -   L is selected from absent, —C(═S)N(R¹³)—, —C(═NR¹⁴)N(R¹³)—,     —SO₂N(R¹³)—, —SO₂—, —C(═O)N(R¹³)—, —N(R¹³)—, —C(═O)C₁₋₂alkylN(R¹³)—,     —N(R¹³)C₁₋₂alkylC(═O)—, —C(═O)C₀₋₁alkylC(═O)N(R¹³)—, —C₀₋₄alkylene-,     —C(═O)C₀₋₁alkylC(═O)OR³—, —C(═NR¹⁴)C₀₋₁alkylC(═O)—, —C(═O)—,     —C(═O)C₀₋₁alkylC(═O)—, and an optionally substituted four to     six-membered heterocyclyl containing between one and three annular     heteroatoms including at least one nitrogen; and -   T is selected from —H, —R¹³, —C₀₋₄alkyl, —C₀₋₄alkylQ, —OC₀₋₄alkylQ,     —C₀₋₄alkylQ, —N(R¹³)C₀₋₄alkylQ, —SO₂C₀₋₄alkylQ, —C(═O)C₀₋₄alkylQ,     —C₀₋₄alkylN(R¹³)Q, and —C(═O)N(R¹³)C₀₋₄alkylQ, -   wherein each of the aforementioned alkyls and alkylenes of —B-L-T is     optionally substituted with one or two of R⁶⁰; -   Z is selected from —S(O)₀₋₂—, —O—, and —NR⁴—; -   R⁴ is either —H or optionally substituted C₁₋₆alkyl; -   each D is independently selected from —O—, —S(O)₀₋₂—, and —NR⁵—; -   each R⁵ is independently —H or optionally substituted C₁₋₆alkyl; -   each R¹³ is independently selected from —H, —C(═O)R²⁰, —C(═O)OR²⁰,     —C(═O)SR²⁰, —SO₂R²⁰, —C(═O)N(R²⁰)R²⁰, and optionally substituted     C₁₋₄alkyl; -   two of R¹³, together with the atom or atoms to which they are     attached, can combine to form a heteroalicyclic optionally     substituted with between one and four of R⁶⁰, said heteroalicyclic     can comprise up to four annular heteroatoms, and said     heteroalicyclic can comprise an aryl or heteroaryl fused thereto, in     which case said aryl or heteroaryl is optionally substituted with an     additional one to four of R⁶⁰; -   each R¹⁴ is independently selected from —H, —NO₂, —N(R²⁰)R²⁰, —CN,     —OR²⁰, optionally substituted C₁₋₆alkyl, optionally substituted     aryl, optionally substituted aryl C₁₋₆alkyl, optionally substituted     heterocyclyl, optionally substituted heterocyclyl C₁₋₆alkyl; -   Q is a five- to ten-membered annular system, optionally substituted     with between zero and four of R²⁰; -   each R⁵⁰ is independently either R²⁰, or according to formula 120;

-   wherein X¹, X², and optionally X³, represent the atoms of a     saturated bridged ring system, said saturated bridged ring system     comprising up to four annular heteroatoms represented by any of X¹,     X², and X³; wherein, -   each X¹ is independently selected from —C(R⁶)R⁷—, —O—, —S(O)₀₋₂—,     and —NR⁸—; -   each X² is independently an optionally substituted bridgehead     methine or a bridgehead nitrogen; -   each X³ is independently selected from —C(R⁶)R⁷—, —O—, —S(O)₀₋₂—,     and —NR⁸—; -   Y is either: -   an optionally substituted lower alkylene linker, between D and     either 1) any annular atom of the saturated bridged ring system,     except X² when X² is a bridgehead nitrogen, or 2) any heteroatom,     represented by any of R⁶ or R⁷; provided there are at least two     carbon atoms between D and any annular heteroatom of the saturated     bridged ring system or any heteroatom represented by any of R⁶ or     R⁷; -   or Y is absent, when Y is absent, said saturated bridged ring     system, is directly attached to D via an annular carbon of said     saturated bridged ring system, unless D is —SO₂—, in which case said     saturated bridged ring system, is directly attached to D via an any     annular atom of said saturated bridged ring system; -   m and p are each independently one to four; -   n is zero to two, when n equals zero there is a single bond between     the two bridgehead X²'s; -   R⁶ and R⁷ are each independently selected from —H, halogen,     trihalomethyl, —CN, —NO₂, —OR²⁰, —N(R²⁰)R²⁰, —S(O)₀₋₂R²⁰,     —SO₂N(R²⁰)R²⁰, —CO₂R²⁰, —C(O)N(R²⁰)R²⁰, —N(R²⁰)SO₂R²⁰,     —N(R²⁰)C(O)R²⁰, —NCO₂R²⁰, —C(O)R²⁰, optionally substituted     C₁₋₆alkyl, optionally substituted aryl, optionally substituted aryl     C₁₋₆alkyl, optionally substituted heterocyclyl, optionally     substituted heterocyclyl C₁₋₆alkyl, and a bond to either Y or D; or -   R⁶ and R⁷, when taken together are oxo; or -   R⁶ and R⁷, when taken together with a common carbon to which they     are attached, form a optionally substituted three- to seven-membered     spirocyclyl, said optionally substituted three- to seven-membered     spirocyclyl optionally containing at least one additional annular     heteroatom selected from N, O, S, and P; -   each R⁸ is independently selected from —R²⁰, Y, —SO₂N(R²⁰)R²⁰,     —CO₂R²⁰, —C(O)N(R²⁰)R²⁰, —SO₂R²⁰, and —C(O)R²⁰; -   each R²⁰ is independently selected from —H, optionally substituted     C₁₋₆alkyl, optionally substituted aryl, optionally substituted aryl     C₁₋₆alkyl, optionally substituted heterocyclyl, and optionally     substituted heterocyclyl C₁₋₆alkyl; or two of R²⁰, when taken     together with a common nitrogen to which they are attached, can form     an optionally substituted five- to seven-membered heterocyclyl, said     optionally substituted five- to seven-membered heterocyclyl     optionally containing at least one additional annular heteroatom     selected from N, O, S, and P; -   each R⁶⁰ is independently selected from —H, halogen, trihalomethyl,     —CN, —NO₂, —OR²⁰, —N(R²⁰)R²⁰, —S(O)₀₋₂R²⁰, —SO₂N(R²⁰)R²⁰, —CO₂R²⁰,     —C(O)N(R²⁰)R²⁰, —N(R²⁰)SO₂R²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)CO₂R²⁰,     —C(O)R²⁰, optionally substituted C₁₋₆alkyl, optionally substituted     aryl, optionally substituted aryl C₁₋₆alkyl, optionally substituted     heterocyclyl, optionally substituted heterocyclyl C₁₋₆alkyl; -   two of R⁶⁰, when taken together with a common carbon to which they     are attached, can form an optionally substituted three- to     seven-membered alicyclic or heteroalicyclic; and two of R⁶⁰, when     taken together can be oxo.     The terms used to describe the scope of formula 103 are defined in     WO 2006/014325 (US Nat'l Stage application Ser. No. 11/571,140)     which is herein incorporated by reference. For example “optionally     substituted heterocyclyl” for formula 103 has the meaning given in     WO 2006/014325 (US Nat'l Stage application Ser. No. 11/571,140).     Whenever a compound of formula 103 is described in this application,     whether by structure or by use of the term “formula 103,” the terms     used to describe that compound are defined by WO 2006/014325 (US     Nat'l Stage application Ser. No. 11/571,140).

In another embodiment, one or more of the chemotherapeutic agent(s) is N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[2-(4-fluorophenyl)ethyl]ethanediamide or pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the cMet inhibitor is N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[2-(4-fluorophenyl)ethyl]ethanediamide or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, one or more of the chemotherapeutic agent(s) is of formula 105:

or a pharmaceutically acceptable salt or hydrate thereof, wherein,

-   V is NR₁, R_(1a), or O—R₁, wherein     -   R₁ is H, CN, halo, —NR₁₃R₁₄, C(O)NR₁₃R₁₄, C₁-C₆ alkyl,         —C(O)—C₁-C₆ alkyl, —C₀-C₆ alkyl-R₂₀, wherein R₂₀ is aryl,         heteroaryl, heterocyclyl, or a 5-12 membered fused bicyclical or         tricyclic saturated, partially saturated, or unsaturated ring         system containing 0-4 ring atoms selected from N, O, and S,         wherein aryl, heteroaryl, C₃-C₇ heterocyclyl, or the 5-12         membered ring system are optionally substituted with one, two,         or three groups independently selected from C₁-C₆ alkyl, and         —C₀-C₆ alkyl-R₂₁;     -   R_(1a) is H or C₁-C₆ alkyl; or     -   when V is NR₁R_(1a), R₁ and R_(1a) together with the nitrogen to         which they are attached form a 4-7 membered heterocyclyl or         heteroaryl group containing, in addition to the nitrogen, up to         two additional heteroatoms independently selected from O, N, and         S, and wherein each heterocyclyl or heteroaryl group is         optionally substituted with one or two of C₁-C₆ alkyl, —NR₁₃R₁₄         or C₃-C₇ cycloalkyl; -   X is H, halo, C₁-C₆ alkyl, NO₂, mono-, di-, or tri-halo substituted     methyl, NR₁₃R₁₄, C(O)O—C₁-C₆ alkyl, or N(R₁₃)—C(O)—C₁-C₆ alkyl; -   Y is H, halo, OH, C₁-C₆ alkyl, C₀-C₆ alkyl-NR₁₅R₁₆, NR₁₅R₁₆, C₁-C₆     alkoxy, —N(R₁₃)—(CH₂)_(n)—NR₁₅R₁₆, —C(O)O—C₁-C₆ alkyl,     —O—(CH₂)_(n)—NR₁₅R₁₆, —C(O)—C₁-C₆ alkyl, —C₀-C₆-alkyl-R₂₁, —O—R₂₁,     —C(O)—R₂₁, —O—(CH₂)—R₂₁, —C(O)—NR₁₃R₁₄, —C(O)—N(R₁₃)-aryl,     —C(O)—N(R₁₃)—(CH₂)_(n)—NR₁₅R₁₆, —C(O)—N(R₁₃)—(CH₂)_(n)-aryl,     —C(O)—N(R₁₃)—(CH₂)_(n)-heterocyclyl; -   or X and Y together with the atoms to which they are attached form a     4-7 membered heterocyclyl or heteroaryl group containing one or two     heteroatoms independently selected from O, N, and S, wherein the     heterocyclyl or heteroaryl group is optionally substituted with one     or two moieties independently selected from halo, C₁-C₆ alkyl,     aryl-C₁-C₆ alkyl-, aryl-(CH₂)_(n)—O—(CH₂)_(n)-aryl-, arylOH, C₃-C₇     cycloalkyl, heterocyclyl, -aryl-N(R₁₃)C(O)—C₃-C₇     cycloalkyl-C(O)—N(R₁₄)-aryl, or a group of the formula -L-M-Q,     wherein     -   L is a bond or C₃-C₇ cycloalkyl,     -   M is C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,     -   Q is NR₁₃R₁₄, N(R₁₃)C(O)—C₁-C₆ alkyl, heterocyclyl, or a         saturated fused bicyclic ring containing one or two heteroatoms         independently selected from O, N, and S,     -   wherein each aryl, heteroaryl, or heterocyclyl substituent on         the group formed by X and Y is optionally further substituted         with one or two moieties independently selected from halo,         C(O)O—(CH₂)_(n)-phenyl, and C(O)—C₁-C₆ alkyl; -   Z is H, NR₂R₃, —S—R_(2a), or —O—R_(2a), wherein     -   R₂ is —C₁-C₆ alkyl, —C₁-C₆ alkyl-NR₁₃R₁₄, —C(O)-aryl,         —C₀-C₆-alkyl-aryl, —C₀-C₆-alkyl-heteroaryl,         —C₀-C₆-alkyl-(C₃-C₇-cycloalkyl), —C₀-C₆-alkyl-heterocyclyl, or         —C₀-C₆ alkyl-5-12 membered fused bicyclic or tricyclic         saturated, partially saturated, or unsaturated ring system         containing 0-4 ring atoms selected from N, O, and S, wherein         -   each alkyl is optionally substituted with phenyl, and         -   each aryl, heteroaryl, C₃-C₇ cycloalkyl, heterocyclyl, or             5-12 membered ring system is optionally substituted with             one, two, or three groups independently selected from halo,             mono-, di-, or tri-halo substituted methyl or methoxy, CN,             NO₂, NR₁₃R₁₄, C(O)O—C₁-C₆ alkyl, N(R₁₃)C(O)—C₁-C₆ alkyl,             —SO₂NR₁₃R₁₄, —O—C(O)—NR₁₃R₁₄, —C₀-C₆ alkyl-C(O)NR₁₅R₁₆,             C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —O—(CH₂)_(n)—NR₁₅R₁₆, —C₁-C₆             alkyl-NR₁₃R₁₄, —N(R₁₃)—C(O)—C₁-C₆ alkyl, —N(R₁₃)—C(O)-aryl,             —C₀-C₆ alkyl-C(O)—N(R₁₃)—(CH₂)_(n)—NR₁₅R₁₆, —C₀-C₆             alkyl-C(O)—N(R₁₃)—(CH₂)_(n)-aryl,             —O—(CH₂)_(n)—C(O)—N(R₁₃)—(CH₂)_(n)—NR₁₅R₁₆,             —O—(CH₂)_(n)—C(O)—NR₁₅R₁₆, —C₀-C₆             alkyl-C(O)—N(R₁₃)—(CH₂)_(n)—O—C₁-C₆ alkyl, —C₀-C₆             alkyl-N(R₁₃)—C(O)O—C₁-C₆ alkyl,             —C₀-C₆alkyl-C(O)-heterocyclyl, —C₀-C₆alkyl-C(O)-heteroaryl,             —C₀-C₆alkyl-C(O)-aryl, —C₀-C₆-alkyl-R₂₁, aryloxy,             —O—(CH₂)_(n)—R₂₁, —SO₂-heterocyclyl,             N(R₁₃)—C(O)—C₃-C₇-cycloalkyl, —C₀-C₆alkyl C(O)O—R₂₁,             C₃-C₇-cycloalkyl, —C₀-C₆alkylR₂₁, —SC₁-C₆alkyl or C₁-C₆             alkyl optionally substituted with halo or cyano,             -   wherein each aryl, heteroaryl, cycloalkyl, or                 heterocyclyl substituent is further optionally                 substituted with 1-3 groups independently selected from                 halo, CF₃, C₁-C₆ alkyl, C₁-C₆ haloalkoxy, NR₁₃R₁₄ and                 C₁-C₆ alkoxy;     -   R₃ is H or C₁-C₆ alkyl;     -   or R₂ and R₃ together with the nitrogen to which they are         attached form a 4-7 membered heterocyclyl or heteroaryl group         containing up to three heteroatoms independently selected from         O, N, and S, and wherein the heterocyclyl or heteroaryl group is         optionally substituted with one or two of halo or C₁-C₆ alkyl;     -   R_(2a) is aryl or C₀-C₆ alkyl-heteroaryl, wherein the aryl and         heteroaryl are optionally substituted with aryl,         —N(R₁₃)—C(O)—C₃-C₇ cycloalkyl or —C(O)NR₁₃R₁₄; -   R₁₃ and R₁₄ are independently H or C₁-C₆ alkyl; -   R₁₅ and R₁₆ are independently H, C₁-C₆ alkyl, heteroaryl, or     heterocyclyl, or R₁₅ and R₁₆ together with the nitrogen to which     they are attached form a 4-7 membered heterocyclyl or heteroaryl     group wherein one or two ring carbons are each optionally replaced     with a heteroatom independently selected from O, N, and S, and     wherein each heterocyclyl or heteroaryl group is optionally     substituted with one or two moieties independently selected from     halo, C₁-C₆ alkyl, or —C(O)O—C₁-C₆ alkyl; -   R₂₁ is heterocyclyl, aryl, heteroaryl, or C₃-C₇ cycloalkyl, and     wherein alkyl, aryl, heteroaryl, C₃-C₇ cycloalkyl, and heterocyclyl     are optionally substituted with one or two moieties independently     selected from halo, —S(O)₂—C₀-C₁ alkyl, —C(O)—C₀-C₁ alkyl, —C(O)—H,     —C₀-C₁ alkyl-aryl, C₁-C₆ alkyl, NR₁₃R₁₄, and heterocyclyl; -   n is 0-6; -   provided that when V is NH₂, X, Y and Z are not simultaneously H.     The terms used to describe the scope of formula 105 are defined in     WO 2006/074057 (US Nat'l Stage application Ser. No. 11/722,719)     which is herein incorporated by reference. For example “optionally     substituted heterocyclyl” for formula 105 has the meaning given in     WO 2006/074057 (US Nat'l Stage application Ser. No. 11/722,719).     Whenever a compound of formula 105 is described in this application,     whether by structure or by use of the term “formula 105,” the terms     used to describe that compound are defined by WO 2006/074057 (US     Nat'l Stage application Ser. No. 11/722,719).

In another embodiment, one or more of the chemotherapeutic agent(s) is of formula 107:

or a pharmaceutically acceptable salt or hydrate thereof, wherein,

-   each W is independently N or CR¹; -   each R¹ is independently selected from —H, halogen, trihaloalkyl,     —CN, —NH₂, —NO₂, —OR⁶, —N═CNR⁶R⁷, —N(R⁶)C(═NR⁸)NR⁶R⁷, —SR⁶,     —S(O)₁₋₂R⁶, —SO₂NR⁶R⁷, —CO₂R⁶, —C(O)NR⁶R⁷, —C(O)N(OR⁶)R⁷,     —C(═NR⁸)NR⁶R⁷, —N(R⁶)SO₂R⁷, —NC(O)R⁶, —NCO₂R⁶, —C(O)R⁷, —R⁷, and     -A-R⁷; provided at least one of R¹ is -A-R⁷, wherein, only for said     at least one -A-R⁷, R⁷ must be an optionally substituted     heteroalicyclic ring, and any nitrogen of said optionally     substituted heteroalicyclic ring cannot be directly bound to A; -   A is O, S(O)₀₋₂, and NR⁶; -   L is O, S(O)₀₋₂, or NR³; -   Q is C or N, when Q is N, then R⁴ does not exist; -   R² and R³ are each independently —H or —R⁷; -   R⁴ and R⁵ are each independently selected from —H, —OR⁶, —NR⁶R⁷,     —S(O)₀₋₂R⁶, —SO₂NR⁶R⁷, —CO₂R⁶, —C(O)NR⁶R⁷, —N(R⁶)SO₂R⁶, —NC(O)R⁶,     —NCO₂R⁶, —C(O)R⁷, —CN, —NO₂, —NH₂, halogen, trihalomethyl, and —R⁷;     or -   R⁴ and R⁵, when taken together, form a five or six-membered aromatic     ring system containing between zero and two nitrogens, said five or     six-membered aromatic ring system optionally substituted with     between zero and four of R¹⁵; -   R⁶ is selected from —H, optionally substituted C₁₋₈alkyl, optionally     substituted arylC₁₋₈alkyl, optionally substituted     heterocyclylC₁₋₈alkyl, optionally substituted aryl, and optionally     substituted heterocyclyl; -   R⁷ is selected from —H, optionally substituted C₁₋₈alkyl, optionally     substituted arylC₁₋₈alkyl, optionally substituted     heterocyclylC₁₋₈alkyl, optionally substituted aryl, and optionally     substituted heterocyclyl; provided that there are at least two     carbons between any heteroatom of R⁷ and A or either nitrogen to     which R² or R³ are attached; or -   R⁶ and R⁷, when taken together with a common nitrogen to which they     are attached, form an optionally substituted five- to seven-membered     heterocyclic ring, said optionally substituted five- to     seven-membered heterocyclic ring optionally containing at least one     additional heteroatom selected from nitrogen, oxygen, sulfur, and     phosphorus; -   R⁸ is —H, —NO₂, —CN, —OR⁶, and optionally substituted C₁₋₈alkyl; -   X is selected from one of the following six formulae:

wherein m is zero to five, n is zero to three, and Z is N or CR¹⁰;

-   R¹⁰ is selected from —H, halogen, trihalomethyl, —NH₂, —NO₂, —OR⁶,     —N═CNR⁶R⁷, —NR⁶R⁷, —N(R⁶)C(—NR⁸)NR⁶R⁷, —SR⁶, —S(O)₁₋₂R⁶, —SO₂NR⁶R⁷,     —CO₂R⁶, —C(O)NR⁶R⁷, —C(O)N(OR⁶)R⁷, —C(═NR⁸)NR⁶R⁷, —N(R⁶)SO₂R⁶,     —NC(O)R⁶, —NCO₂R⁶, —C(O)R⁷, and R⁷; -   K is O, S, or NR¹¹; -   R¹¹ is selected from cyano, —NO₂, —OR⁶, —S(O)₁₋₂R⁶, —SO₂NR⁶R⁷,     —CO₂R⁶, —C(O)NR⁶R⁷, —C(O)N(OR⁶)R⁷, —C(O)R⁷, and R⁶; and -   each R¹⁵ is independently selected from —H, halogen, —NH₂, —NO₂,     —OR⁶, —N═CNR⁶R⁷, —NR⁶R⁷, —N(R⁶)C(═NR⁸)NR⁶R⁷, —SR⁶, —S(O)₁₋₂R⁶,     —SO₂NR⁶R⁷, —CO₂R⁶, —C(O)NR⁶R⁷, —C(O)N(OR⁶)R⁷, —C(═NR⁸)NR⁶R⁷,     —N(R⁶)SO₂R⁶, —NC(O)R⁶, —NCO₂R⁶, —C(O)R⁷, and R⁷.     The terms used to describe the scope of formula 107 are defined in     WO 2004/050681 (US Nat'l Stage application Ser. No. 10/533,555)     which is herein incorporated by reference. For example “optionally     substituted aryl” for formula 107 has the meaning given in WO     2004/050681 (US Nat'l Stage application Ser. No. 10/533,555).     Whenever a compound of formula 107 is described in this application,     whether by structure or by use of the term “formula 107,” the terms     used to describe that compound are defined by WO 2004/050681 (US     Nat'l Stage application Ser. No. 10/533,555).

In another embodiment, one or more of the chemotherapeutic agent(s) is of formula 108:

or a pharmaceutically acceptable salt or hydrate thereof, wherein,

-   X₂₁ is N or CR₂₂; -   X₂₂ is N or CR₂₃; -   X₂₃ is N or CR₂₄, but when X₂₂ is N then X₂₃ is CR₂₄; -   each of R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀, and     each R₃₁, R₃₂ and R₃₃ is independently selected from —H, halogen,     trihalomethyl, —CN, —NO₂, —NR₃₅R_(35a), —S(O)₀₋₂R₃₅,     —SO₂NR₃₅R_(35a), —CO₂R₃₅, —C(O)NR₃₅R_(35a), —N(R₃₅)SO₂R₃₅,     —N(R₃₅)C(O)R₃₅, —N(R₃₅)CO₂R₃₅, —OR₃₅, —C(O)R₃₅, optionally     substituted lower alkyl, optionally substituted aryl, optionally     substituted heterocyclyl, optionally substituted heterocyclylalkyl,     and optionally substituted arylalkyl; -   R is selected from —H, halogen, trihalomethyl, —S(O)₀₋₂R₃₅,     —SO₂NR₃₅R_(35a), —CO₂R₃₅, —C(O)NR₃₅R_(35a), —OR₃₅, —C(O)R₃₅,     optionally substituted lower alkyl, optionally substituted aryl,     optionally substituted heterocyclyl, optionally substituted     heterocyclylalkyl, and optionally substituted arylalkyl; or -   two of R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁ or R₃₂, together with the     atom or respective atoms to which they are attached, combine to form     an optionally substituted spirocyclic ring system, optionally     substituted fused ring system, and optionally substituted saturated     bridged ring system; -   each of R₃₅ and R_(35a) is independently selected from —H,     optionally substituted lower alkyl, optionally substituted lower     alkoxy, optionally substituted aryl, -   optionally substituted lower arylalkyl, optionally substituted lower     aryl alkoxy, optionally substituted heterocyclyl, and optionally     substituted lower heterocyclylalkyl; or -   R₃₅ and R_(35a), together with the atom or respective atoms to which     they are attached, combine to form an optionally substituted five-     to seven-membered heterocyclyl; and -   m is an integer from 0 to 5; -   n is an integer from 1 to 2; and -   with the provisos that when X₂₂ is CR₂₃ and X₂₃ is N then R is not     optionally substituted aryl, aralkyl or heteroaryl, and that when     X₂₂ is N and X₂₃ is CR₂₄ then R is not optional substituted aryl or     heteroaryl and R₂₁ is not —NR₃₅R_(35a), and that when X₂₂ is CR₂₃     and X₂₃ is CR₂₄ then R₂₁ is not optionally substituted aryl; -   and that compounds     4-(4-(2-fluorophenyl)piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine,     4-(4-(3-chlorophenyl)piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine,     6-(4-(2-nitro-4-(trifluoromethyl)phenyl)piperazin-1-yl)-7H-purine,     6-(4-(4-fluorophenyl)piperazin-1-yl)-7H-purine,     6-(4-(2,5-dimethylphenyl)piperazin-1-yl)-7H-purine,     6-(4-(3,4-dichlorophenyl)piperazin-1-yl)-7H-purine,     6-(4-(2-fluorophenyl)piperazin-1-yl)-7H-purine,     6-(4-(3-chlorophenyl)piperazin-1-yl)-7H-purine,     6-(4-(4-methoxyphenyl)piperazin-1-yl)-7H-purine,     6-(4-(4-nitrophenyl)piperazin-1-yl)-7H-purine,     6-(4-phenylpiperazin-1-yl)-7H-purine,     4-(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine,     4-phenyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ol,     6-(4-(2-methoxyphenyl)piperazin-1-yl)-7H-purine,     6-(4-(2-chlorophenyl)piperazin-1-yl)-7H-purine,     6-(4-o-tolylpiperazin-1-yl)-7H-purine,     6-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)-7H-purine,     6-(4-(2-methoxyphenyl)piperazin-1-yl)-7H-purine are not included in     Formula I.     The terms used to describe the scope of formula 108 are defined in     WO 2005/117909 (US Nat'l Stage application Ser. No. 11/568,173)     which is herein incorporated by reference. For example “optionally     substituted aryl” for formula 108 has the meaning given in WO     2005/117909 (US Nat'l Stage application Ser. No. 11/568,173).     Whenever a compound of formula 108 is described in this application,     whether by structure or by use of the term “formula 108,” the terms     used to describe that compound are defined by WO 2005/117909 (US     Nat'l Stage application Ser. No. 11/568,173).

In another embodiment, one or more of the chemotherapeutic agent(s) is of formula 109:

or a pharmaceutically acceptable salt or hydrate thereof, wherein: R₁ is H, halo, cyano, aryl, heteroaryl, C₁₋₄ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the aryl, heteroaryl, alkyl, alkenyl and alkynyl are optionally substituted with one or two groups independently selected from CO₂R₁₀, CONR₁₀R₁₁, OR₁₀, and NR₁₀R₁₁; R₂ is H, NH₂, SH, OH, or C₁-C₂ alkyl; R₃, R₄, R₅, and R₆ are each independently H, oxo, CO₂R₁₀, CONR₁₀R₁₁, C₁₋₄ alkyl, C₁-C₆ alkoxy, or C₁-C₆ alkoxy-C₁-C₄ alkyl, wherein the C₁-C₄ alkyl, C₁-C₆ alkoxy and C₁-C₆ alkoxy-C₁-C₄ alkyl in each group are independently optionally substituted with 1 or 2 substituents independently selected from CO₂R₁₀, CONR₁₀R₁₁, R₁₀, and NR₁₀R₁₁, or

-   -   R₃ and R₅ together with the carbons to which they are attached         form a C₃-C₇ carbocyclic ring, wherein the ring is optionally         substituted with H, halo, cyano, nitro, or amino,     -   R₄ and R₆ together with the carbons to which they are attached         form a C₃-C₇ carbocyclic ring, wherein the ring is optionally         substituted with H, halo, cyano, nitro, or amino R₃ and R₆         together with the carbons to which they are attached form a         bridged C₅-C₇ carbocyclic ring, wherein the ring is optionally         substituted with H, halo, cyano, nitro, or amino, or     -   R₄ and R₅ together with the carbons to which they are attached         form a bridged C₅-C₇ carbocyclic ring, wherein the ring is         optionally substituted with H, halo, cyano, nitro, or amino;         L is C₀₋₄ alkyl, C₂-C₆ alkenyl, —N(R₁₂)—, —C(O)N(R₁₂)—,         —N(R₁₂)C(O)—, —C(O)—, —O—(CH₂)_(n)—, or —(CH₂)_(n)—O—, wherein n         is 1-4;         Q₁ is N or CR₁₃, wherein R₁₃ is H or C(O)NR₁₂(CH₂)_(n)NR₁₀R₁₁;         Q₂ is a bond, CR₁₄, O or N, wherein R₁₄ is H, OH, C₁₋₄ alkyl,         C₁₋₄ alkoxy, NR₁₅R₁₅,         wherein R₁₅ is H or C₁₋₄ alkyl, or Q₂ and V together form C(═O);         when Q₂ is a bond,     -   V is absent and R₁₃ is not H;         when Q₁ is CR₁₃ and Q₂ is CH,     -   V is H, OH, NH₂, C₁-C₆ alkoxy, NR₁₀R₁₁, O(CH₂)_(n)NR₁₀R₁₁,         O(CH₂)_(n) attached to a C or N of a 4-7 membered heterocyclyl,         NR₁₂(CH₂)_(n)NR₁₀R₁₁, NR₁₂C(O)NR₁₂(CH₂)_(n)NR₁₀R₁₁,         NR₁₂C(O)(CH₂)_(n)NR₁₀R₁₁, (CH₂)_(m)—O—(CH₂)_(n)NR₁₀R₁₁,         (CH₂)_(m)NR₁₂(CH₂)_(n)NR₁₀R₁₁, (CH₂)_(m)CHR₁₂(CH₂)_(n)NR₁₀R₁₁,         C₁₋₄ alkyl optionally substituted with OH or NR₁₀R₁₁, or     -   V is a 4-7 membered unsaturated cyclic containing 1-3 atom of O         or N, or     -   V is a bicyclic solubilizing group;

-   when Q₁ is N and Q₂ is CH, or when Q₁ is CR₁₃ and Q₂ is O or N,     -   V is H, (CH₂)_(m)—O—(CH₂)_(n)NR₁₀R₁₁,         (CH₂)_(m)NR₁₂(CH₂)_(n)NR₁₀R₁₁, (CH₂)_(m)CHR₁₂(CH₂)_(n)NR₁₀R₁₁,         C(O)NR₁₂(CH₂)_(n)NR₁₀R₁₁, C(O)(CH₂)_(n)NR₁₀R₁₁,         C(O)O(CH₂)_(n)NR₁₀R₁₁, C(O)C(O)NR₁₂(CH₂)_(n)NR₁₀R₁₁,         SO₂(CH₂)_(n)NR₁₀R₁₁, C(O)—C₂-C₆ alkenyl, or C₁₋₄ alkyl         optionally substituted with OH or NR₁₀R₁₁, or     -   V is a 4-7 membered saturated or unsaturated cyclic or         heterocyclic containing 1-3 atoms of O or N, optionally         substituted with 1 or 2 C₁-C₃ alkoxy groups or     -   V is a “bicyclic solubilizing group”;

-   m is 1-3,

-   n is 1-4,

-   W is C₁-C₆ alkyl, NR₁₀R₁₁, or W is aryl, C₃-C₇ cycloalkyl,     heterocyclyl, heteroaryl, or 5-12 membered fused bicyclic or     tricyclic saturated, partially saturated, or unsaturated ring system     containing 0-4 ring atoms selected from N, O, and S, wherein each     aryl, cycloalkyl, heterocyclyl, heteroaryl, and fused bicyclic or     tricyclic ring system is optionally substituted with 1, 2, or 3     substituents independently selected from halo, CN, NO₂, CF₃, OH,     NR₁₀R₁₁, C₁-C₆ alkoxy, C₁-C₆ alkyl, NO₂, C(O)OC₁-C₆ alkyl,     C(O)NR₁₂—C₁-C₆ alkoxy, C(O)NR₁₂-heterocyclyl, aryl, O-aryl,     O—CH₂-aryl, N-aryl, wherein each aryl substituent is optionally     further substituted with halo, or     -   V, Q₂, L, and W together form an aryl ring, heteroaryl ring,         C₃-C₇ cycloalkyl ring, heterocyclyl ring, or a 5-12 membered         fused bicyclic or tricyclic saturated, partially saturated or         unsaturated ring system containing 0-4 ring atoms selected from         N, O, and S, wherein each ring or ring system is optionally         substituted with 1, 2, or 3 groups independently selected from         halo, CN, NO₂, CF₃, OH, NR₁₀R₁₁, C₁-C₆ alkoxy, C₁-C₆ alkyl, NO₂,         C(O)OC₁-C₆ alkyl, C(O)NR₁₂—C₁-C₆ alkoxy, C(O)NR₁₂-heterocyclyl,         aryl, O-aryl, NH-aryl, wherein each aryl substituent is         optionally further substituted with halo; and

-   R₁₀, R₁₁, and R₁₂ are each independently H or C₁₋₆ alkyl which is     optionally substituted with aryl or heteroaryl,     provided the compound is not a compound selected from:

-   4-(4-(2-fluorophenyl)piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine;

-   4-(4-(3-chlorophenyl)piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine;

-   ethyl 4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate;

-   tert-butyl     4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate; and

-   N-(4-phenoxyphenyl)-4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxamide.     The terms used to describe the scope of formula 109 are defined in     WO 2006/071819 (US Nat'l Stage application Ser. No. 11/722,291 which     is herein incorporated by reference. For example “optionally     substituted aryl” for formula 109 has the meaning given in WO     2006/071819 (US Nat'l Stage application Ser. No. 11/722,291.     Whenever a compound of formula 109 is described in this application,     whether by structure or by use of the term “formula 109,” the terms     used to describe that compound are defined by WO 2006/071819 (US     Nat'l Stage application Ser. No. 11/722,291.

For each of the foregoing embodiments, the Compound of Formula I can be selected from any of the following embodiments, including from the Representative Compounds in Table 1.

In another embodiment of the Invention, the Compound of Formula I is that where R⁷ is halo and all other groups are as defined in the Summary of the Invention for Group A, Group B, Group C, or Group D. In another embodiment, R⁷ is iodo or bromo. In another embodiment, R⁷ is iodo. In another embodiment, the compound is that where R⁷ is iodo or bromo and all other groups are as defined in the Summary of the Invention for Group A.

In another embodiment of the Invention, the Compound of Formula I is that where X is halo and all other groups are as defined in the Summary of the Invention for Group A, Group B, Group C, or Group D. In another embodiment, X is fluoro or chloro. In another embodiment, X is fluoro. In another embodiment, the compound is that where X is fluoro or chloro and all other groups are as defined in the Summary of the Invention for Group A.

In another embodiment of the Invention, the Compound of Formula I is that where R⁷ and X are halo and all other groups are as defined in the Summary of the Invention for Group A, Group B, Group C, or Group D. More specifically, R⁷ is iodo and X is fluoro. In another embodiment, the compound is that where R⁷ is iodo and X is fluoro and all other groups are as defined in the Summary of the Invention for Group A.

In another embodiment of the Invention, the Compound of Formula I is that where R¹, R², R⁵, and R⁶ are hydrogen and all other groups are as defined in the Summary of the Invention for Group A, Group B, Group C, or Group D. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen and all other groups are as defined in the Summary of the Invention for Group A.

In another embodiment of the Invention, the compound of Formula I is selected from Group A where all groups are as defined in the Summary of the Invention.

In another embodiment of the invention (A1), the Compound of Formula I is that where X and R⁷ are halo and all other groups are as defined in the Summary of the Invention for a compound of Group A.

In another embodiment (A2), the compound of Formula I is selected from Group A where R¹⁰ and R¹² are independently hydrogen or halo. In another embodiment, R¹⁰ and R¹² are independently hydrogen or fluoro. In another embodiment, R¹⁰ is 3-fluoro and R¹² is hydrogen. In another embodiment, R¹⁰ and R¹² are fluoro, in another embodiment, 3-fluoro and 4-fluoro, 4-fluoro and 5-fluoro, or 4-fluoro and 6-fluoro.

In another embodiment of the invention (A3), the compound of Formula I is that where R¹, R², R⁵ and R⁶ are hydrogen and all other groups are as defined in the Summary of the Invention for Group A.

In another embodiment (A4), the compound of Formula I is selected from Group A where X, R⁷, and A are as defined in the Summary of the Invention; and

-   one of R¹, R², R³, R⁴, R⁵, and R⁶ is halo, nitro, —NR⁸R^(8′), —OR⁸,     —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,     —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″),     —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂),     —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵),     —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl,     cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,     alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are     independently optionally substituted with one, two, three, four,     five, six or seven groups independently selected from halo, alkyl,     haloalkyl, nitro, optionally substituted cycloalkyl, optionally     substituted heterocycloalkyl, optionally substituted aryl,     optionally substituted arylalkyl, optionally substituted heteroaryl,     optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′),     —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and the     others of R¹, R², R³, R⁴, R⁵, and R⁶ are as defined in the Summary     of the Invention; or -   one of R¹ and R² together with the carbon to which they are     attached, R³ and R⁴ together with the carbon to which they are     attached, and R⁵ and R⁶ together with the carbon to which they are     attached forms C(O) or C(═NOH); and the others of R¹, R², R³, R⁴,     R⁵, and R⁶ are as defined in the Summary of the Invention.

In another embodiment of the Invention (A5), the compound of Formula I is selected from Group A where X, R⁷, and A are as defined in the Summary of the Invention; and

-   R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,     —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),     —NR⁸C(O)NR^(8′)R^(8″)—NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),     —CH₂N(R²⁵)(NR^(25a)R^(25b)), CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN),     —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,     alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where     the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and     heterocycloalkyl are independently optionally substituted with one,     two, three, four, five, six or seven groups independently selected     from halo, alkyl, haloalkyl, nitro, optionally substituted     cycloalkyl, optionally substituted heterocycloalkyl, optionally     substituted aryl, optionally substituted arylalkyl, optionally     substituted heteroaryl, optionally substituted heteroarylalkyl,     —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,     —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and     —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the     Invention; or -   R³ and R⁴ together with the carbon to which they are attached form     C(O) or C(═NOH); and -   R¹, R², R⁵ and R⁶ are as defined in the Summary of the Invention.

In another embodiment of embodiment A5, the Compound of Formula I is that where R¹, R², R⁵ and R⁶ are hydrogen.

In another embodiment of the Invention (A6), the compound of Formula I is selected from Group A where X, R⁷, and A are as defined in the Summary of the Invention; and

-   R³ and R⁴ are independently halo, nitro, —NR⁸R^(8′), —OR⁸,     —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,     —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″),     —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂),     —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵),     —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl,     cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,     alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are     independently optionally substituted with one, two, three, four,     five, six or seven groups independently selected from halo, alkyl,     haloalkyl, nitro, optionally substituted cycloalkyl, optionally     substituted heterocycloalkyl, optionally substituted aryl,     optionally substituted arylalkyl, optionally substituted heteroaryl,     optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′),     —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or -   R³ and R⁴ together with the carbon to which they are attached form     C(O) or C(═NOH); -   R¹, R², R⁵ and R⁶ are as defined in the Summary of the Invention.

In another embodiment of embodiment A, the Compound of Formula I is that where R¹, R², R⁵ and R⁶ are hydrogen.

In another embodiment of the Invention (A7), the compound of Formula I is selected from Group A where X and R⁷ are halo; A is phenylene optionally substituted with R¹⁰ and R¹² where R¹⁰ and R¹² are independently hydrogen or halo;

-   R¹, R², R⁵ and R⁶ are hydrogen; -   R³ is hydrogen and R⁴ is —NR⁸R^(8′) (where R⁸ is hydrogen, hydroxy,     alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl and     R^(8′) is hydroxy, alkoxy, aryl, cycloalkyl, heteroaryl, or     heterocycloalkyl), —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),     —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), alkenyl, and     alkynyl; where the alkenyl and alkynyl are optionally substituted     with one, two, three, four, five, six or seven groups independently     selected from halo, alkyl, haloalkyl, nitro, optionally substituted     cycloalkyl, optionally substituted heterocycloalkyl, optionally     substituted aryl, optionally substituted arylalkyl, optionally     substituted heteroaryl, optionally substituted heteroarylalkyl,     —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,     —C(O)NR⁸R^(8′) NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR¹⁸ and     —NR⁸C(O)R^(8′); or -   R³ and R⁴ together with the carbon to which they are attached form     C(O) or C(═NOH); -   m, R^(8″), and R⁹ are as defined in the Summary of the Invention for     a compound of Group A; and unless otherwise specified in this     embodiment, R⁸ and R^(8′) are as defined in the Summary of the     Invention for a compound of Group A.

In another embodiment of the Invention (A8), the compound of Formula I is selected from Group A where R³ is hydrogen, halo, hydroxy, alkoxy, or amino. In another embodiment, R³ is hydrogen, fluoro, hydroxy, methoxy, or amino. In another embodiment, R³ is hydrogen or hydroxy. In another embodiment, R³ is hydroxy.

In another embodiment of embodiment A8, the Compound of Formula I is that where X and R⁷ are halo; A is phenylene optionally substituted with R¹⁰ and R¹² where R¹⁰ and R¹² are independently hydrogen or halo; R¹, R², R⁵ and R⁶ are hydrogen; and R⁴, is as defined in the Summary of the Invention for a compound of Group A.

Another embodiment of the Invention (A9) is that where the compound of Formula I is selected from Group A where R¹, R², R⁵ and R⁶ are hydrogen; R³ is hydrogen, halo, hydroxy, alkoxy, or amino; and R⁴ is heterocycloalkyl, heteroaryl, or alkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′) and all other groups are as defined in the Summary of the Invention for a compound of Group A.

In another embodiment of embodiment A9, the Compound of Formula I is that where R⁴ is alkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′) and all other groups are as defined in the Summary of the Invention for a compound of Group A. In another embodiment, the compound is of Formula I(a) or I(b):

where R³ is as defined in A9; X, R⁷, R⁸, R^(8′), R¹⁰, R¹², R¹⁴, and R¹⁶ are as defined in the Summary of the Invention for a compound of Group A.

In another embodiment of embodiment A9, the Compound of Formula I is that where R⁴ is heterocycloalkyl.

In another embodiment of embodiment A9, the compound of Formula I is that where X and R⁷ are halo; A is phenylene optionally substituted with R¹⁰ and R¹² where R¹⁰ and R¹² are independently hydrogen or halo; R³ is hydroxy; and R⁴ is alkyl substituted with —NR⁸R^(8′) or R⁴ is heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8′), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and where m, R³, R⁸, R^(8′), R^(8″), and R⁹ are as defined in the Summary of the Invention for a compound of Group A.

In another embodiment of the Invention (A10), the compound of Formula I is selected from Group A where

-   R⁴ is     -   a) hydrogen;     -   b) —CH₂N(R²⁵)(NR^(25a)R^(25b));     -   c) —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b));     -   d) —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂);     -   e) —CH₂NR²⁵C(═NH)(N(R^(25a))(CN);     -   f) —CH₂NR²⁵C(═NH)(R²⁵);     -   g) —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂);     -   h) alkyl;     -   i) alkyl substituted with one or two —OR⁸ where R⁸ is hydrogen,         aryl, or alkyl where the alkyl is substituted with one or two         hydroxy;     -   j) alkyl substituted with one, two, or three halo;     -   k) alkyl substituted with nitro;     -   l) alkyl substituted with —S(O)_(m)R⁹ (where m is 0 and R⁹ is         aryl);     -   m) alkyl substituted with optionally substituted         heterocycloalkyl;     -   n) alkenyl;     -   o) —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen;         alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl         substituted with one or two —NR³⁰R^(30′) where R³⁰ and R^(30′)         are independently hydrogen, alkyl, or hydroxyalkyl; alkyl         substituted with optionally substituted heteroaryl; or alkyl         substituted with optionally substituted cycloalkyl);     -   p) —C(O)NR⁸R^(8′) (where R⁸ is hydrogen, alkyl, or alkenyl; and         R^(8′) is hydrogen; hydroxy; alkyl; alkenyl; alkyl substituted         with one or two hydroxy; alkyl substituted with optionally         substituted heterocycloalkyl; alkyl substituted with         —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently hydrogen,         alkyl, or hydroxyalkyl; or optionally substituted alkoxy);     -   q) —NR⁸C(O)OR^(8′) (where R⁸ and R^(8′) are independently         hydrogen, alkyl, or alkenyl);     -   r) alkyl substituted with —NR⁸R^(8′) (where R⁸ is hydrogen,         alkyl, alkenyl, alkynyl, or alkyl substituted with one or two         hydroxy; and R^(8′) is hydrogen; hydroxy; alkoxy; alkyl;         alkenyl; alkynyl; optionally substituted alkoxy; alkyl         substituted with one or two hydroxy; alkyl substituted with one         or two alkoxy; alkyl substituted with —NR³⁰R^(30′) where R³⁰ and         R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl;         alkyl substituted with one or two hydroxy and one or two         —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently hydrogen,         alkyl, or hydroxyalkyl; alkyl substituted with one, two, three,         four, or five halo; alkyl substituted with optionally         substituted cycloalkyl; alkyl substituted with optionally         substituted aryl; alkyl substituted with one or two hydroxy and         one optionally substituted aryl; alkyl substituted with         optionally substituted heterocycloalkyl; alkyl substituted with         optionally substituted heteroaryl; heteroaryl; aryl; aryl         substituted with one or two hydroxy; aryl substituted with one         or two alkoxy; aryl substituted with one or two halo; aryl         substituted with one or two —NR³²C(O)R^(32a) where R³² is         hydrogen or alkyl and R^(32a) is alkyl, alkenyl, alkoxy, or         cycloalkyl; aryl substituted with —NR³⁴SO₂R^(34a) where R³⁴ is         hydrogen or alkyl and R^(34a) is alkyl, alkenyl, cycloalkyl,         aryl, heteroaryl, or heterocycloalkyl; cycloalkyl; cycloalkyl         substituted with one or two hydroxy; cycloalkyl substituted with         one or two hydroxy and one or two hydroxyalkyl; cycloalkyl         substituted with one or two alkoxy; cycloalkyl substituted with         carboxy; cycloalkyl substituted with —C(O)NR³³R^(33a) where R³³         is hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or         cycloalkyl; alkyl substituted with —C(O)NR³³R^(33a) where R³³ is         hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or         cycloalkyl; cycloalkyl substituted with optionally substituted         cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted with         alkyl; heterocycloalkyl substituted with alkoxycarbonyl;         heterocycloalkyl substituted with optionally substituted         arylalkyl; heterocycloalkyl substituted with one or two hydroxy;         heterocycloalkyl substituted with one or two alkoxy;         heterocycloalkyl substituted with one or two hydroxyalkyl;         heterocycloalkyl substituted with one or two hydroxy, one or two         alkoxy, and one or two hydroxyalkyl; alkyl substituted with         optionally substituted aryloxy; alkyl substituted with         —S(O)_(n)R³¹ where n is 0 and R³¹ is alkyl; alkyl substituted         with carboxy; alkyl substituted with alkoxycarbonyl; or alkyl         substituted with —NR³²C(O)R^(32a) where R³² is hydrogen or alkyl         and R^(32a) is alkyl, alkenyl, alkoxy, or cycloalkyl);     -   s) —NR⁸C(O)R^(8′) (where R⁸ is hydrogen, alkyl, or alkenyl; and         R^(8′) is hydrogen; alkyl; alkyl substituted with one or two         hydroxy; alkyl substituted with optionally substituted         heterocycloalkyl; alkyl substituted with —NR³⁰R^(30′) where R³⁰         and R^(30′) are independently hydrogen, alkyl, hydroxyalkyl, or         alkenyl);     -   t) cycloalkyl;     -   u) cycloalkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′)         are independently hydrogen, alkyl, or alkenyl;     -   v) heterocycloalkyl;     -   w) heterocycloalkyl substituted with —NR⁸R^(8′) where R⁸ and         R^(8′) are independently hydrogen, alkyl, or alkenyl;     -   x) heterocycloalkyl substituted with one or two alkyl;     -   y) heterocycloalkyl substituted with —C(O)OR⁸ where R⁸ is alkyl         or alkenyl;     -   z) alkyl substituted with —NR⁸C(O)R^(8′) (where R⁸ is hydrogen,         alkyl, or alkenyl and R^(8′) is alkyl; alkenyl; or alkyl         substituted with alkoxy, aryl, and one, two, or three halo);     -   aa) heteroaryl;     -   bb) heteroaryl substituted with —NR⁸R^(8′) where R⁸ and R^(8′)         are independently hydrogen, alkyl, or alkenyl; alkyl substituted         with optionally substituted heteroaryl;     -   cc) alkyl substituted with —NR⁸S(O)₂R⁹ where R⁸ is hydrogen,         alkyl, or alkenyl and R⁹ is alkyl or alkenyl;     -   dd) alkyl substituted with —NR⁸C(O)OR^(8′) where R⁸ and R^(8′)         are independently hydrogen, alkyl, or alkenyl;     -   ee) alkyl substituted with one aryl and one —NR⁸R^(8′) where R⁸         and R^(8′) are independently hydrogen, alkyl, or alkenyl; or     -   ff) alkyl substituted with one or two —OR⁸ (where R⁸ is         hydrogen) and one or two —NR⁸R^(8′) where R⁸ and R^(8′) are         independently hydrogen, alkyl, or alkenyl.

In another embodiment, R⁴ is hydrogen, —CH₂N(H)(NHCH₃), —CH₂NHC(═NH)(NH₂), —CH₂NHC(═NH)(NHNO₂), —CH₂NHC(═NH)(NHCN), —CH₂NHC(═NH)(phenyl), —CH₂NHC(NH₂)═CH(NO₂), methyl, ethyl, hydroxymethyl, 2,3-dihydroxypropyl, 3-hydroxy-2-methyl-prop-2-yl, N-(1-methoxy-prop-2-yl)-aminomethyl, N-(ethoxypropyl)-aminomethyl, N-(ethoxyethyl)-aminomethyl, N-(2,2-dimethoxyethyl)-aminomethyl, N-(methoxyethyl)-aminomethyl, N-(isopropoxyethyl)-aminomethyl, trifluoromethyl, 1-nitro-ethyl, 1-methyl-1-nitro-ethyl, 1-nitro-propyl, 3-methyl-1-nitro-butyl, phenylthiomethyl, allyl, ethenyl, 2-methylthio-ethylaminomethyl, 3-methylthio-propylaminomethyl, N-(tert-butoxycarbonylaminopropyl)-aminomethyl, N-(1-carboxyethyl)-aminomethyl, N-(1R-carboxyethyl)-aminomethyl, N-(1S-carboxyethyl)-aminomethyl, N-(1-methoxycarbonylethyl)-aminomethyl, —NH₂, —NH(CH₂)₃CH₃, —NHCH₃, —NH(CH₂CH₃), —NHCH₂CH(CH₃)₂, —NHCH₂CH₂OH, —NHCH₂CH₂CH₂NH₂, —N(CH₃)CH₂CH₂(heteroaryl), —NHCH₂(cycloalkyl), —C(O)NH₂, —C(O)NHOH, —C(O)NH(OCH₂CH(OH)CH₂OH), —C(O)NH(CH₂)₃CH₃, —C(O)NHCH₂CH═CH₂, —C(O)NHCH₂CH₃, —C(O)NHCH₂CH₂OH, —C(O)NHCH₂CH(OH)CH₂OH, —C(O)NHCH₂CH₂CH(OH)CH₂OH, —C(O)NHCH₂CH₂(piperidin-1-yl), —C(O)NH(phenyl), —C(O)NHCH₂CH₂N(CH₂CH₃)₂, —NHC(O)OC(CH₃)₃, —NHC(O)OCH₃, azetidinylmethyl, pyrrolidinylmethyl, 3-hydroxy-pyrrolidinylmethyl, 2-(methoxymethyl)-pyrrolidinylmethyl, 2S-(methoxymethyl)-pyrrolidinylmethyl, 2R-(methoxymethyl)-pyrrolidinylmethyl, morpholinylmethyl, hydroxypiperidinylmethyl, 4-alkyl-piperazinylmethyl, 4-alkyl-homopiperazinylmethyl, 4-(heterocycloalkyl)-piperidinylmethyl, 4-(dialkylaminoalkyl)-piperazinylmethyl, N-hydroxyaminomethyl, N-methoxyaminomethyl, N-ethoxyaminomethyl, N-ethylaminomethyl, 1-(N-ethyl-amino)-ethyl, N,N-diethylaminomethyl, N,N-dimethylaminomethyl, aminomethyl, 1-amino-ethyl, 1R-amino-ethyl, 1S-amino-ethyl, 1-(methylamino)-ethyl, 1-(N,N-dimethylamino)-ethyl, 1-amino-1-methyl-ethyl, 1-aminopropyl, 1S-aminopropyl, 1R-aminopropyl, N-(n-propyl)-aminomethyl, N-(isopropyl)-aminomethyl, 2-(N-isopropylamino)-ethyl, 3-(N-isopropylamino)-2-methyl-prop-2-yl, 1-(N-ethyl-amino)-propyl, 1-(N,N-diethyl-amino)-propyl, 1-aminobutyl, 1-amino-isobutyl, N-(2-aminoethyl)-aminomethyl, N-(n-butyl)-aminomethyl, N-isobutylaminomethyl, tert-butylaminomethyl, 1-(tert-butylamino)-ethyl, sec-butylaminomethyl, N-(2-methyl-but-3-yl)-aminomethyl, N-(3,3-dimethyl-butyl)-aminomethyl, N-(3-methylbut-3-yl)-aminomethyl, N-(2-methylbutyl)-aminomethyl, N-(pent-3-yl)-aminomethyl, n-pentylaminomethyl, isopentylaminomethyl, sec-pentylaminomethyl, neopentylaminomethyl, N-(2,2,4-trimethyl-pent-4-yl)-aminomethyl, N-(2-ethyl-butyl)-aminomethyl, N-allyl-aminomethyl, 3-methyl-but-1-yn-3-ylaminomethyl, N-(2,3-dihydroxypropyloxy)-aminomethyl, N-cyclopropylaminomethyl, N-cyclobutylaminomethyl, N-cyclopentylaminomethyl, N-cyclopenten-4-ylaminomethyl, N-(1(R,S)-hydroxy-cyclopent-2-yl)-aminomethyl, N-(1S-hydroxy-cyclopent-2-yl)-aminomethyl, N-(1R-hydroxy-cyclopent-2-yl)-aminomethyl, N-(1(R,S)-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl, N-(1S-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl, N-(1R-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl, N-(3,4-dihydroxy-cyclopentyl)-aminomethyl, N-(1-hydroxymethyl-cyclopent-1-yl)-aminomethyl, N-(2,3-dihydroxy-4-hydroxymethyl-cyclopentyl)-aminomethyl, N-(1(R,S)-methoxy-cyclopent-2-yl)-aminomethyl, N-(1S-methoxy-cyclopent-2-yl)-aminomethyl, N-(1R-methoxy-cyclopent-2-yl)-aminomethyl, N-(1-carboxy-cyclopentyl)-aminomethyl, N-cyclohexylaminomethyl, N-(1(R,S)-hydroxy-cyclohex-2-yl)-aminomethyl, N-(cis-4-hydroxy-cyclohexyl)-aminomethyl, N-(trans-4-hydroxy-cyclohexyl)-aminomethyl, 1-[N-(cis-4-hydroxy-cyclohexyl)-amino]-ethyl, 1-[N-(trans-4-hydroxy-cyclohexyl)-amino]-ethyl, N-(1(R)-hydroxy-cyclohex-2-yl)-aminomethyl, N-(1(S)-hydroxy-cyclohex-2-yl)-aminomethyl, N-(1-hydroxymethyl-cyclohexyl)-aminomethyl, N-(2-cyclohexyl-cyclohexyl)-aminomethyl, N-{(2R,3S,4R,6R)-2-(hydroxymethyl)-3,4-dihydroxy-6-methoxy-tetrahydro-2H-pyran-5-yl}-aminomethyl, N-(cycloheptyl)-aminomethyl, N-(cyclooctyl)-aminomethyl, [(1r,3r,5R,7R)-tricyclo[3.3.1.1^(3,7)]dec-2-ylamino]methyl, N-[1-(cyclopropylaminocarbonyl)-cyclopentyl]-aminomethyl, —CH₂NHC(CH₃)₂C(O)NH(cyclohexyl), —CH₂NHC(CH₃)₂C(O)NH(CH₂CH₃), N-(1-benzyloxy-cyclopent-2-yl)-aminomethyl, N-(cyclopropylmethyl)-aminomethyl, N-(cyclohexylmethyl)-aminomethyl, N-(1-cyclohexylethyl)-aminomethyl, N-(imidazolyl)-aminomethyl, N-(1,3,5-triazinyl)-aminomethyl, N-(5-hydroxy-pyrazol-3-yl)-aminomethyl, N-(5-methyl-pyrazol-3-yl)-aminomethyl, N-(benzimidazolyl)-aminomethyl, N-(pyrimidin-2-yl)-aminomethyl, N-(pyridin-2-yl)-aminomethyl, N-(pyridin-3-yl)-aminomethyl, N-(pyridin-4-yl)-aminomethyl, N-indan-1-yl-aminomethyl, N-indan-2-yl-aminomethyl, phenylaminomethyl, N-(2-hydroxyphenyl)-aminomethyl, N-(3-hydroxyphenyl)-aminomethyl, N-(4-hydroxyphenyl)-aminomethyl, N-(2-methoxyphenyl)-aminomethyl, N-(3-methoxyphenyl)-aminomethyl, N-(4-methoxyphenyl)-aminomethyl, N-(2-fluorophenyl)-aminomethyl, N-(3-fluorophenyl)-aminomethyl, N-(4-fluorophenyl)-aminomethyl, N-(2-chlorophenyl)-aminomethyl, N-(3-chlorophenyl)-aminomethyl, N-(4-chlorophenyl)-aminomethyl, N-(3-methylcarbonylamino-phenyl)-aminomethyl, N-(4-methylcarbonylamino-phenyl)-aminomethyl, N-(2-aminophenyl)-aminomethyl, N-(3-aminophenyl)-aminomethyl, N-(4-aminophenyl)-aminomethyl, N-(2-methylsulfonylaminophenyl)-aminomethyl, N-(3-methylsulfonylaminophenyl)-aminomethyl, N-(4-methylsulfonylaminophenyl)-aminomethyl, N-(2-fluoro-4-hydroxy-phenyl)-aminomethyl, N-(3-fluoro-4-hydroxy-phenyl)-aminomethyl, N-(benzyl)-aminomethyl, N-(2-hydroxyphenylmethyl)-aminomethyl, N-(3-hydroxyphenylmethyl)-aminomethyl, N-(4-hydroxyphenylmethyl)-aminomethyl, N-(2-(N-methylpiperazin-1-yl)-phenylmethyl)-aminomethyl, N-(4-alkyl-phenethyl)-aminomethyl, N-(1-hydroxy-3-phenyl-prop-2-yl)-aminomethyl, N-(pyrrolidin-2-ylmethyl)-aminomethyl, N—(N-alkyl-pyrrolidinylmethyl)-aminomethyl, N—(N-alkyl-pyrrolidinylethyl)-aminomethyl, N-(pyrrolidinylpropyl)-aminomethyl, N-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-aminomethyl, N-(tetrahydrofuranylmethyl)-aminomethyl, N-(tetrahydro-2H-pyran-4-ylmethyl)-aminomethyl, N-(tetrahydro-2H-pyranylethyl)-aminomethyl, N-(piperidin-4-ylmethyl)-aminomethyl, N—(N-methylpiperidin-4-ylmethyl)-aminomethyl, N—(N-tert-butoxycarbonylpiperidin-4-ylmethyl)-aminomethyl, N—(N-methylimidazol-4-ylmethyl)-aminomethyl, N—(N-methylimidazol-5-ylmethyl)-aminomethyl, N-[2-(imidazol-4-yl)-ethyl]-aminomethyl, N-[3-(imidazolyl)-propyl]-aminomethyl, N-(pyridin-3-ylethyl)-aminomethyl, N-(pyridin-4-ylethyl)-aminomethyl, N-(thien-2-ylethyl)-aminomethyl, N-(furan-2-ylethyl)-aminomethyl, N-(5-methyl-1,3,4-oxadiazol-2-ylmethyl)-aminomethyl, N-(2-indolin-3-ylethyl)-aminomethyl, 2-(N,N-dimethylamino)-ethylaminomethyl, 2-(N,N-dimethylamino)-1-methyl-ethylaminomethyl, 3-aminopropylaminomethyl, 3-(N,N-dimethylamino)-propylaminomethyl, 3-(N,N-diethylamino)-propylaminomethyl, N—(N,N-diisopropylaminoethyl)-aminomethyl, N—(N,N-dimethylaminobutyl)-aminomethyl, N-(3-hydroxypropyl)-aminomethyl, N-(2-hydroxypropyl)-aminomethyl, N-(1,2-dihydroxypropyl)-aminomethyl, N-(1-amino-2-hydroxy-prop-3-yl)-aminomethyl, N—(N-ethoxycarbonyl-piperidin-4-yl)-aminomethyl, N—(N-benzylpiperidin-4-yl)-aminomethyl, N-(homopiperidin-3-yl)-aminomethyl, N—(N-benzylpyrrolidin-3-yl)-aminomethyl, N—(N-ethylpiperidin-3-yl)aminomethyl, 2,2,2-trifluoroethylaminomethyl, 3,3,3-trifluoropropylaminomethyl, 2,2,3,3,3-pentafluoropropylaminomethyl, —CH₂N(CH₂CH₂OH)₂, —CH₂N(CH₃)(CH₂CH₂OH), —CH₂NH(CH₂CH₂OH), —CH₂NH(CH₂CH₂CH₂CH₂OH), —CH₂N(CH₃)(N-methyl-pyrrolidin-3-yl), —CH₂NH(C(CH₃)₂CH₂OH), —NHC(O)CH(CH₃)₂, —NHC(O)CH₂N(CH₂CH₃)₂, —NHC(O)CH₂NH(CH₃), —NHC(O)H, —NHC(O)CH₂CH(OH)CH₂OH, —NHC(O)CH₂NH₂, —NHC(O)CH₂N(CH₂CH₂OH)₂, —NHC(O)CH₂CH₂N(CH₂CH₂OH)₂, —NHC(O)CH₂(4-alkyl-piperazinyl), —NHC(O)CH₂(Piperidinyl), N-(phenyloxyethyl)-aminomethyl, cyclopentyl, 1-amino-cyclopentyl, (cis,trans)-2-amino-cyclopentyl, (cis,trans)-2-amino-cyclopentyl, cis-2-amino-cyclopentyl, trans-2-amino-cyclopentyl, (cis,trans)-2-hydroxy-cyclohexyl, cis-2-hydroxy-cyclohexyl, trans-2-hydroxy-cyclohexyl, (cis,trans)-2-amino-cyclohexyl, cis-2-amino-cyclohexyl, trans-2-amino-cyclohexyl, azetidin-3-yl, pyrrolidinyl, N-alkyl-pyrrolidinyl, 3-(dialkylamino)-pyrrolidinyl, piperidinyl, 2-methyl-piperidin-6-yl, N-tert-butoxycarbonylpiperidin-2-yl, piperazinyl, —CH₂NHC(O)CH₃, —CH(CH₃)NHC(O)CH₃, —CH(CH₃)NHC(O)C(OCH₃)(CF₃)phenyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, N-methyl-imidazol-2-yl, 5-methyl-imidazol-2-yl, 1,2,4-triazol-3-yl, thiazol-2-yl, 2-aminopyrimidin-3-yl, pyridinyl, benzimidazolyl, imidazol-1-ylmethyl, imidazol-2-ylmethyl, triazolylmethyl, (5-amino-3-methylpyrazol-1-yl)-methyl, phenoxymethyl, methylsulfonylaminomethyl, 1-(methoxycarbonylamino)-ethyl, 1-amino-1-phenyl-methyl, or 1-amino-3-hydroxy-propyl.

In another embodiment of embodiment A10, the Compound of Formula I is that where X and R⁷ are halo; A is phenylene optionally substituted with R¹⁰ and R¹² where R¹⁰ and R¹² are independently hydrogen or halo; R¹, R², R⁵ and R⁶ are hydrogen; and R³ is hydrogen, halo, hydroxy, alkoxy, or amino.

In another embodiment of embodiment A10, the Compound of Formula I is that where R³ is hydrogen and R⁴ is

-   -   a) hydrogen;     -   b) —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen;         alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl         substituted with one or two —NR³⁰R^(30′) where R³⁰ and R^(30′)         are independently hydrogen, alkyl, or hydroxyalkyl; alkyl         substituted with optionally substituted heteroaryl; or alkyl         substituted with optionally substituted cycloalkyl);     -   c) —C(O)NR⁸R^(8′) (where R⁸ is hydrogen, alkyl, or alkenyl; and         R^(8′) is hydrogen; hydroxy; alkyl; alkenyl; alkyl substituted         with one or two hydroxy; alkyl substituted with         heterocycloalkyl; alkyl substituted with —NR³⁰R^(30′) where R³⁰         and R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl;         or optionally substituted alkoxy);     -   d) —NR⁸C(O)OR^(8′) (where R⁸ and R^(8′) are independently         hydrogen, alkyl, or alkenyl);     -   e) —NR⁸C(O)R^(8′) (where R⁸ is hydrogen, alkyl, or alkenyl; and         R^(8′) is hydrogen; alkyl; alkyl substituted with one or two         hydroxy; alkyl substituted with optionally substituted         heterocycloalkyl; alkyl substituted with —NR³⁰R^(30′) where R³⁰         and R^(30′) are independently hydrogen, alkyl, hydroxyalkyl, or         alkenyl);     -   f) alkyl;     -   g) alkyl substituted with one or two —OR⁸ (where R⁸ is         hydrogen);     -   h) alkyl substituted with —NR⁸R^(8′) (where R⁸ is hydrogen,         alkyl, alkenyl, alkynyl, or alkyl substituted with one or two         hydroxy; and R^(8′) is hydrogen; alkyl; alkenyl; alkynyl; alkyl         substituted with one or two hydroxy; heterocycloalkyl         substituted with alkyl; or alkyl substituted with —NR³⁰R^(30′)         where R³⁰ and R^(30′) are independently hydrogen, alkyl, or         hydroxyalkyl);     -   i) heterocycloalkyl; or     -   j) heterocycloalkyl substituted with —NR⁸R^(8′) (where R⁸ and         R^(8′) are independently hydrogen, alkyl, or alkenyl).

In another embodiment, R³ is hydrogen and R⁴ is hydrogen, hydroxymethyl, —NH₂, —NH(CH₂)₃CH₃, —NHCH₃, —NH(CH₂CH₃), —NHCH₂CH(CH₃)₂, —NHCH₂CH₂OH, —NHCH₂CH₂CH₂NH₂, —N(CH₃)CH₂CH₂(pyridin-2-yl), —NHCH₂(cyclopropyl), —NHCH₂(cyclopentyl), —NHCH₂(cyclohexyl), —C(O)NHOH, —C(O)NH(OCH₂CH(OH)CH₂OH), —C(O)NH(CH₂)₃CH₃, —C(O)NHCH₂CH═CH₂, —C(O)NHCH₂CH₃, —C(O)NHCH₂CH₂OH, —C(O)NHCH₂CH(OH)CH₂OH, —C(O)NHCH₂CH₂CH(OH)CH₂OH, —C(O)NHCH₂CH₂(piperidin-1-yl), —C(O)NH(phenyl), —C(O)NHCH₂CH₂N(CH₂CH₃)₂, N-(isopropyl)-aminomethyl, N,N-dimethylaminomethyl, N-(2-aminoethyl)-aminomethyl, —NHC(O)OC(CH₃)₃, —NHC(O)OCH₃, —NHC(O)CH(CH₃)₂, —NHC(O)CH₂NH₂, —NHC(O)CH₂N(CH₂CH₃)₂, —NHC(O)CH₂NH(CH₃), —NHC(O)H, —NHC(O)CH₂CH(OH)CH₂OH, —NHC(O)CH₂N(CH₂CH₂OH)₂, —NHC(O)CH₂CH₂N(CH₂CH₂OH)₂, —NHC(O)CH₂(4-alkyl-piperazinyl), —NHC(O)CH₂(piperidinyl), pyrrolidinyl, 3-(dialkylamino)-pyrrolidinyl, piperidinyl, 2-methyl-piperidin-6-yl, N-methylpiperidin-2-yl, or piperazin-2-yl.

In another embodiment of embodiment A10, the Compound of Formula I is that where R³ is alkoxy and R⁴ is alkyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen, alkyl, or alkenyl). In another embodiment, R³ is methoxy and R⁴ is alkyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen, alkyl, or alkenyl).

In another embodiment of embodiment A10, the Compound of Formula I is that where R³ is halo and R⁴ is alkyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen, alkyl, or alkenyl). In another embodiment, R³ is fluoro and R⁴ is alkyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen, alkyl, or alkenyl).

In another embodiment of embodiment A10, the Compound of Formula I is that where R³ is amino and R⁴ is alkyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen, alkyl, or alkenyl).

In another embodiment of embodiment A10, the Compound of Formula I is that where R³ is hydroxy and R⁴ is

-   -   a) hydrogen;     -   b) —CH₂N(R²⁵)(NR^(25a)R^(25b));     -   c) —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b));     -   d) —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂);     -   e) —CH₂NR²⁵C(═NH)(N(R^(25a))(CN);     -   f) —CH₂NR²⁵C(═NH)(R²⁵);     -   g) —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂);     -   h) alkyl;     -   i) alkenyl;     -   j) alkyl substituted with one or two —OR⁸ where R⁸ is hydrogen,         aryl, or alkyl where the alkyl is substituted with one or two         hydroxy;     -   k) alkyl substituted with one, two, or three halo;     -   l) alkyl substituted with nitro;     -   m) alkyl substituted with —S(O)_(m)R⁹ (where m is 0 and R⁹ is         aryl);     -   n) alkyl substituted with optionally substituted         heterocycloalkyl;     -   o) alkyl substituted with —NR⁸R^(8′) (where R⁸ is hydrogen,         alkyl, alkenyl, alkynyl, or alkyl substituted with one or two         hydroxy; and R^(8′) is hydrogen; hydroxy; alkoxy; alkyl;         alkenyl; alkynyl; optionally substituted alkoxy; alkyl         substituted with one or two hydroxy; alkyl substituted with         —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently hydrogen,         alkyl, or hydroxyalkyl; alkyl substituted with one or two         hydroxy and one or two —NR³⁰R^(30′) where R³⁰ and R^(30′) are         independently hydrogen, alkyl, or hydroxyalkyl; heterocycloalkyl         substituted with alkyl, alkoxycarbonyl, or optionally         substituted arylalkyl; alkyl substituted with one, two, three,         four, or five halo; alkyl substituted with optionally         substituted cycloalkyl; alkyl substituted with optionally         substituted aryl; alkyl substituted with one or two hydroxy and         one optionally substituted aryl; alkyl substituted with         optionally substituted heterocycloalkyl; alkyl substituted with         optionally substituted heteroaryl; heteroaryl; aryl; aryl         substituted with one or two hydroxy; aryl substituted with one         or two alkoxy; aryl substituted with one or two halo; aryl         substituted with one or two —NR³²C(O)R^(32a) where R³² is         hydrogen or alkyl and R^(32a) is alkyl, alkenyl, alkoxy, or         cycloalkyl; aryl substituted with —NR³⁴SO₂R^(34a) where R³⁴ is         hydrogen or alkyl and R^(34a) is alkyl, alkenyl, cycloalkyl,         aryl, heteroaryl, or heterocycloalkyl; cycloalkyl; cycloalkyl         substituted with one or two hydroxy; cycloalkyl substituted with         one or two hydroxy and one or two hydroxyalkyl; cycloalkyl         substituted with one or two alkoxy; cycloalkyl substituted with         carboxy; cycloalkyl substituted with —C(O)NR³³R^(33a) where R³³         is hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or         cycloalkyl; cycloalkyl substituted with optionally substituted         cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted with         one or two hydroxy; heterocycloalkyl substituted with one or two         alkoxy; heterocycloalkyl substituted with one or two         hydroxyalkyl; heterocycloalkyl substituted with one or two         hydroxy, one or two alkoxy, and one or two hydroxyalkyl; alkyl         substituted with —C(O)NR³³R^(33a) where R³³ is hydrogen or alkyl         and R^(33a) is alkyl, alkenyl, alkynyl, or cycloalkyl; alkyl         substituted with optionally substituted aryloxy; alkyl         substituted with —S(O)_(n)R³¹ where n is 0 and R³¹ is alkyl;         alkyl substituted with carboxy; alkyl substituted with         alkoxycarbonyl; or alkyl substituted with —NR³²C(O)R^(32a) where         R³² is hydrogen or alkyl and R^(32a) is alkyl, alkenyl, alkoxy,         or cycloalkyl);     -   p) heterocycloalkyl;     -   q) —C(O)NR⁸R^(8′) (where R⁸ is hydrogen, alkyl, or alkenyl; and         R^(8′) is hydrogen; alkyl; alkyl; alkenyl; or substituted with         one or two hydroxy);     -   r) alkyl substituted with —NR⁸C(O)R^(8′) (where R⁸ is hydrogen,         alkyl, or alkenyl and R^(8′) is alkyl; alkenyl; or alkyl         substituted with alkoxy, aryl, and one, two, or three halo);     -   s) cycloalkyl;     -   t) cycloalkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′)         are independently hydrogen, alkyl, or alkenyl;     -   u) cycloalkyl substituted with —C(O)NR³³R^(33a) where R³³ is         hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or         cycloalkyl;     -   v) heterocycloalkyl;     -   w) heterocycloalkyl substituted with one or two alkyl;     -   x) heterocycloalkyl substituted with —C(O)OR⁸ where R⁸ is alkyl         or alkenyl;     -   y) heteroaryl;     -   z) heteroaryl optionally substituted with —NR⁸R^(8′) where R⁸         and R^(8′) are independently hydrogen, alkyl, or alkenyl;     -   aa) alkyl substituted with optionally substituted heteroaryl;     -   bb) alkyl substituted with —NR⁸S(O)₂R⁹ where R⁸ is hydrogen,         alkyl, or alkenyl and R⁹ is alkyl or alkenyl;     -   cc) alkyl substituted with —NR⁸C(O)OR^(8′) where R⁸ and R^(8′)         are independently hydrogen, alkyl, or alkenyl;     -   dd) alkyl substituted with one aryl and one —NR⁸R^(8′) where R⁸         and R^(8′) are independently hydrogen, alkyl, or alkenyl; or     -   ee) alkyl substituted with one or two —OR⁸ (where R⁸ is         hydrogen) and one or two —NR⁸R^(8′) where R⁸ and R^(8′) are         independently hydrogen, alkyl, or alkenyl.

In another embodiment, R³ is hydroxy and R⁴ is hydrogen, —CH₂N(H)(NHCH₃), —CH₂NHC(═NH)(NH₂), —CH₂NHC(═NH)(NHNO₂), —CH₂NHC(═NH)(NHCN), —CH₂NHC(═NH)(phenyl), —CH₂NHC(NH₂)═CH(NO₂), methyl, ethyl, hydroxymethyl, 2,3-dihydroxypropyl, 3-hydroxy-2-methyl-prop-2-yl, N-(1-methoxy-prop-2-yl)-aminomethyl, N-(ethoxypropyl)-aminomethyl, N-(ethoxyethyl)-aminomethyl, N-(2,2-dimethoxyethyl)-aminomethyl, N-(methoxyethyl)-aminomethyl, N-(isopropoxyethyl)-aminomethyl, trifluoromethyl, 1-nitro-ethyl, 1-methyl-1-nitro-ethyl, 1-nitro-propyl, 3-methyl-1-nitro-butyl, phenylthiomethyl, allyl, ethenyl, 2-methylthio-ethylaminomethyl, 3-methylthio-propylaminomethyl, N-(tert-butoxycarbonylaminopropyl)-aminomethyl, N-(1-carboxyethyl)-aminomethyl, N-(1R-carboxyethyl)-aminomethyl, N-(1S-carboxyethyl)-aminomethyl, N-(1-methoxycarbonylethyl)-aminomethyl, azetidinylmethyl, pyrrolidinylmethyl, 3-hydroxy-pyrrolidinylmethyl, 2-(methoxymethyl)-pyrrolidinylmethyl, 2S-(methoxymethyl)-pyrrolidinylmethyl, 2R-(methoxymethyl)-pyrrolidinylmethyl, morpholinylmethyl, 4-hydroxypiperidinylmethyl, 4-methyl-piperazinylmethyl, 4-methyl-homopiperazinylmethyl, 4-(piperidinyl)-piperidinylmethyl, 4-[2-(N,N-diethylamino)-ethyl]-piperazinylmethyl, N-hydroxyaminomethyl, N-methoxyaminomethyl, N-ethoxyaminomethyl, N-ethylaminomethyl, 1-(N-ethyl-amino)-ethyl, N,N-diethylaminomethyl, N,N-dimethylaminomethyl, aminomethyl, 1-amino-ethyl, 1R-amino-ethyl, 1S-amino-ethyl, 1-(methylamino)-ethyl, 1-(N,N-dimethylamino)-ethyl, 1-amino-1-methyl-ethyl, 1-aminopropyl, 1S-aminopropyl, 1R-aminopropyl, N-(n-propyl)-aminomethyl, N-(isopropyl)-aminomethyl, 2-(N-isopropylamino)-ethyl, 3-(N-isopropylamino)-2-methyl-prop-2-yl, 1-(N-ethyl-amino)-propyl, 1-(N,N-diethyl-amino)-propyl, 1-aminobutyl, 1-amino-isobutyl, N-(n-butyl)-aminomethyl, N-isobutylaminomethyl, tert-butylaminomethyl, 1-(tert-butylamino)-ethyl, sec-butylaminomethyl, N-(2-methyl-but-3-yl)-aminomethyl, N-(3,3-dimethyl-butyl)-aminomethyl, N-(3-methylbut-3-yl)-aminomethyl, N-(2-methylbutyl)-aminomethyl, N-(pent-3-yl)-aminomethyl, n-pentylaminomethyl, isopentylaminomethyl, sec-pentylaminomethyl, neopentylaminomethyl, N-(2,2,4-trimethyl-pent-4-yl)-aminomethyl, N-(2-ethyl-butyl)-aminomethyl, N-allyl-aminomethyl, 3-methyl-but-1-yn-3-ylaminomethyl, N-(2,3-dihydroxypropyloxy)-aminomethyl, N-cyclopropylaminomethyl, N-cyclopentylaminomethyl, N-cyclopenten-4-ylaminomethyl, N-(1(R,S)-hydroxy-cyclopent-2-yl)-aminomethyl, N-(1S-hydroxy-cyclopent-2-yl)-aminomethyl, N-(1R-hydroxy-cyclopent-2-yl)-aminomethyl, N-(1(R,S)-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl, N-(1S-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl, N-(1R-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl, N-(3,4-dihydroxy-cyclopentyl)-aminomethyl, N-(1-hydroxymethyl-cyclopent-1-yl)-aminomethyl, N-(2,3-dihydroxy-4-hydroxymethyl-cyclopentyl)-aminomethyl, N-(1(R,S)-methoxy-cyclopent-2-yl)-aminomethyl, N-(1S-methoxy-cyclopent-2-yl)-aminomethyl, N-(1R-methoxy-cyclopent-2-yl)-aminomethyl, N-(1-carboxy-cyclopentyl)-aminomethyl, N-cyclohexylaminomethyl, N-(1(R,S)-hydroxy-cyclohex-2-yl)-aminomethyl, N-(1(R)-hydroxy-cyclohex-2-yl)-aminomethyl, N-(1(S)-hydroxy-cyclohex-2-yl)-aminomethyl, N-(cis-4-hydroxy-cyclohexyl)-aminomethyl, N-(trans-4-hydroxy-cyclohexyl)-aminomethyl, 1-[N-(cis-4-hydroxy-cyclohexyl)-amino]-ethyl, 1-[N-(trans-4-hydroxy-cyclohexyl)-amino]-ethyl, N-(1-hydroxymethyl-cyclohexyl)-aminomethyl, N-(2-cyclohexyl-cyclohexyl)-aminomethyl, N-{(2R,3S,4R,6R)-2-(hydroxymethyl)-3,4-dihydroxy-6-methoxy-tetrahydro-2H-pyran-5-yl}-aminomethyl, N-(cycloheptyl)-aminomethyl, N-(cyclooctyl)-aminomethyl, [(1r,3r,5R,7R)-tricyclo[3.3.1.1^(3,7)]dec-2-ylamino]methyl, N-(1-benzyloxy-cyclopent-2-yl)-aminomethyl, N-[1-(cyclopropylaminocarbonyl)-cyclopentyl]-aminomethyl, —CH₂NHC(CH₃)₂C(O)NH(cyclohexyl), —CH₂NHC(CH₃)₂C(O)NH(CH₂CH₃), N-(cyclopropylmethyl)-aminomethyl, N-(cyclohexylmethyl)-aminomethyl, N-(1-cyclohexylethyl)-aminomethyl, N-(imidazolyl)-aminomethyl, N-(1,3,5-triazinyl)-aminomethyl, N-(5-hydroxy-pyrazol-3-yl)-aminomethyl, N-(5-methyl-pyrazol-3-yl)-aminomethyl, N-(benzimidazolyl)-aminomethyl, N-(pyrimidin-2-yl)-aminomethyl, N-(pyridin-2-yl)-aminomethyl, N-(pyridin-3-yl)-aminomethyl, N-(pyridin-4-yl)-aminomethyl, N-indan-1-yl-aminomethyl, N-indan-2-yl-aminomethyl, phenylaminomethyl, N-(2-hydroxyphenyl)-aminomethyl, N-(3-hydroxyphenyl)-aminomethyl, N-(4-hydroxyphenyl)-aminomethyl, N-(2-methoxyphenyl)-aminomethyl, N-(3-methoxyphenyl)-aminomethyl, N-(4-methoxyphenyl)-aminomethyl, N-(2-fluorophenyl)-aminomethyl, N-(3-fluorophenyl)-aminomethyl, N-(4-fluorophenyl)-aminomethyl, N-(2-chlorophenyl)-aminomethyl, N-(3-chlorophenyl)-aminomethyl, N-(4-chlorophenyl)-aminomethyl, N-(3-methylcarbonylamino-phenyl)-aminomethyl, N-(4-methylcarbonylamino-phenyl)-aminomethyl, N-(2-aminophenyl)-aminomethyl, N-(3-aminophenyl)-aminomethyl, N-(4-aminophenyl)-aminomethyl, N-(2-methylsulfonylaminophenyl)-aminomethyl, N-(3-methylsulfonylaminophenyl)-aminomethyl, N-(4-methylsulfonylaminophenyl)-aminomethyl, N-(2-fluoro-4-hydroxy-phenyl)-aminomethyl, N-(3-fluoro-4-hydroxy-phenyl)-aminomethyl, N-(benzyl)-aminomethyl, N-(2-hydroxyphenylmethyl)-aminomethyl, N-(3-hydroxyphenylmethyl)-aminomethyl, N-(4-hydroxyphenylmethyl)-amino methyl, N-(2-(N-methylpiperazin-1-yl)-phenylmethyl)-aminomethyl, N-(4-methyl-phenethyl)-aminomethyl, N-(1-hydroxy-3-phenyl-prop-2-yl)-aminomethyl, N-(pyrrolidin-2-ylmethyl)-aminomethyl, N—(N-ethyl-pyrrolidinylmethyl)-aminomethyl, N—(N-methyl-pyrrolidin-2-ylethyl)-aminomethyl, N-(pyrrolidinylpropyl)-aminomethyl, N-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-aminomethyl, N-(tetrahydrofuranylmethyl)-aminomethyl, N-(tetrahydro-2H-pyran-4-ylmethyl)-aminomethyl, N-(tetrahydro-2H-pyranylethyl)-aminomethyl, N-(piperidin-4-ylmethyl)-aminomethyl, N—(N-methylpiperidin-4-ylmethyl)-aminomethyl, N—(N-tert-butoxycarbonylpiperidin-4-ylmethyl)-aminomethyl, N—(N-methylimidazol-5-ylmethyl)-aminomethyl, N—(N-methylimidazol-4-ylmethyl)-aminomethyl, N-[2-(imidazol-4-yl)-ethyl]-aminomethyl, N-[3-(imidazolyl)-propyl]-aminomethyl, N-(pyridin-3-ylethyl)-aminomethyl, N-(pyridin-4-ylethyl)-aminomethyl, N-(thien-2-ylethyl)-aminomethyl, N-(furan-2-ylethyl)-aminomethyl, N-(5-methyl-1,3,4-oxadiazol-2-ylmethyl)-aminomethyl, N-(2-indolin-3-ylethyl)-aminomethyl, 2-(N,N-dimethylamino)-ethylaminomethyl, 2-(N,N-dimethylamino)-1-methyl-ethylaminomethyl, 3-aminopropylaminomethyl, 3-(N,N-dimethylamino)-propylaminomethyl, 3-(N,N-diethylamino)-propylaminomethyl, N—(N,N-diisopropylaminoethyl)-aminomethyl, N—(N,N-dimethylaminobutyl)-aminomethyl, 3-hydroxypropylaminomethyl, N-(1,2-dihydroxypropyl)-aminomethyl, N-(1-amino-2-hydroxy-prop-3-yl)-aminomethyl, N—(N-ethoxycarbonyl-piperidin-4-yl)-aminomethyl, N—(N-benzylpiperidin-4-yl)-aminomethyl, N-(homopiperidin-3-yl)-aminomethyl, N—(N-benzylpyrrolidin-3-yl)-aminomethyl, N—(N-ethylpiperidin-3-yl)aminomethyl, 2,2,2-trifluoroethylaminomethyl, 3,3,3-trifluoropropylaminomethyl, 2,2,3,3,3-pentafluoropropylaminomethyl, —CH₂N(CH₂CH₂OH)₂, —CH₂N(CH₃)(CH₂CH₂OH), —CH₂NH(CH₂CH₂OH), —CH₂NH(CH₂CH₂CH₂CH₂OH), —CH₂NH(C(CH₃)₂CH₂OH), —CH₂N(CH₃)(N-methyl-pyrrolidin-3-yl), —C(O)NH₂, —C(O)NHCH₂CH═CH₂, —C(O)NHCH₂CH(OH)CH₂OH, N-(phenyloxyethyl)-aminomethyl, —CH₂NHC(O)CH₃, —CH(CH₃)NHC(O)CH₃, —CH(CH₃)NHC(O)C(OCH₃)(CF₃)phenyl, cyclopentyl, 1-amino-cyclopentyl, (cis,trans)-2-amino-cyclopentyl, (cis,trans)-2-amino-cyclopentyl, cis-2-amino-cyclopentyl, trans-2-amino-cyclopentyl, (cis,trans)-2-hydroxy-cyclohexyl, cis-2-hydroxy-cyclohexyl, trans-2-hydroxy-cyclohexyl, (cis,trans)-2-amino-cyclohexyl, cis-2-amino-cyclohexyl, trans-2-amino-cyclohexyl, azetidin-3-yl, pyrrolidinyl, N-methyl-pyrrolidin-2-yl, N-ethyl-pyrrolidin-2-yl, 3-(dimethylamino)-pyrrolidinyl, piperidinyl, 2-methyl-piperidin-6-yl, N-methylpiperidin-2-yl, N-tert-butoxycarbonylpiperidin-2-yl, piperazin-2-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, N-methyl-imidazol-2-yl, 5-methyl-imidazol-2-yl, 1,2,4-triazol-3-yl, thiazol-2-yl, 2-aminopyrimidin-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, benzimidazolyl, imidazol-1-ylmethyl, imidazol-2-ylmethyl, triazol-1-ylmethyl, (5-amino-3-methyl-pyrazol-3-yl)-methyl, phenoxymethyl, 2-hydroxyethyloxymethyl, methylsulfonylaminomethyl, 1-(methoxycarbonylamino)-ethyl, 1-amino-1-phenyl-methyl, or 1-amino-3-hydroxy-propyl.

Another embodiment of the Invention (A11) is that where the compound of Formula I is selected from Group A where R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH). In another embodiment, X and R⁷ are halo; A is phenylene optionally substituted with R¹⁰ and R¹² where R¹⁰ and R¹² are independently hydrogen or halo; R¹, R², R⁵ and R⁶ are hydrogen; and R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH).

Another embodiment of the Invention (A12) is that where the compound of Formula I is selected from Group A where X and R⁷ are halo; A is phenylene optionally substituted with R¹⁰ and R¹² where R¹⁰ and R¹² are independently hydrogen or halo; and R¹, R², R⁴, R⁵ and R⁶ are hydrogen.

Another embodiment of the Invention (A13) is that where the compound of Formula I is selected from Group A where A is phenylene.

Another embodiment of the Invention (A14) is that where the compound of Formula I is selected from Group A where R¹ is hydrogen and R² is alkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′) and all other groups are as defined in the Summary of the Invention for a compound of Group A.

Another embodiment of the Invention (A15) is that where the compound of Formula I is selected from Group A where A is phenylene; R⁷ is iodo or bromo; X is fluoro or chloro; and R¹, R², R⁵, and R⁶ are hydrogen; and R¹⁰, R¹², R¹⁴, and R¹⁶ are independently hydrogen or fluoro. In another embodiment, R¹⁰ is 3-fluoro and R¹², R¹⁴, and R¹⁶ are hydrogen or halo; R¹⁰ is 3-fluoro, R¹² is 4-fluoro, and R¹⁴ and R¹⁶ are hydrogen; R¹⁰ is 4-fluoro, R¹² is 5-fluoro, and R¹⁴ and R¹⁶ are hydrogen; R¹⁰ is 4-fluoro, R¹² is 6-fluoro, and R¹⁴ and R¹⁶ are hydrogen; or R¹² is 4-fluoro and R¹⁰, R¹⁴, and R¹⁶ are hydrogen.

In another embodiment of the invention is a compound of Formula selected form Group A where R³ is hydroxy and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R³ is hydroxy and R⁴ is heterocycloalkyl or alkyl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with groups independently selected from hydroxy and alkyl).

In another embodiment of the Invention (B1) the compound of Formula I is selected from Group B where all groups are as defined in the Summary of the Invention.

In another embodiment of the invention (B2), the Compound of Formula I is that where X and R⁷ are halo; and all other groups are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, X is fluoro or chloro and R⁷ is iodo or bromo.

In another embodiment of the invention (B3), the compound of Formula I is selected from Group B where R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)), CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′) and R⁴ is as defined in the Summary of the Invention; or R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of the invention (B4), the compound of Formula I is selected from Group B where R³ and R⁴ are independently halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)R^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of the invention (B5), the Compound of Formula I is that where A is heteroarylene selected from thien-diyl, benzo[d]isoxazol-diyl, benzo[d]isothiazol-diyl, 1H-indazol-diyl (optionally substituted at the N1 position with R¹⁹ where R¹⁹ is as defined in the Summary of the Invention for a compound of Group B), benzo[d]oxazol-diyl, benzo[d]thiazol-diyl, 1H-benzo[d]imidazol-diyl (optionally substituted at the N1 position with R¹⁹ where R¹⁹ is as defined in the Summary of the Invention for a compound of Group B), 1H-benzo[d][1,2,3]triazol-diyl (optionally substituted at the N1 position with R¹⁹ where R¹⁹ is as defined in the Summary of the Invention for a compound of Group B), imidazo[1,2-a]pyridin-diyl, cinnolin-diyl, quinolin-diyl, pyridin-diyl, 1-oxido-pyridin-diyl, [1,2,4]triazolo[4,3-a]pyridin-diyl, and 2,3-dihydroimidazo[1,2-a]pyridin-diyl; and A is further optionally substituted with one, two, three, or four groups selected from R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴, and R¹⁶ and all other groups are as defined in the Summary of the Invention for a compound of Group B. In another embodiment A is selected from thien-3,4-diyl, benzo[d]isoxazol-5,6-diyl, benzo[d]isothiazol-5,6-diyl, 1H-indazol-5,6-diyl (optionally substituted at the N1 position with R¹⁹ where R¹⁹ is alkyl or alkenyl), benzo[d]oxazol-5,6-diyl, benzo[d]thiazol-5,6-diyl, 1H-benzo[d]imidazol-5,6-diyl (optionally substituted at the N1 position with R¹⁹ where R¹⁹ is alkyl or alkenyl), 1H-benzo[d][1,2,3]triazol-5,6-diyl (optionally substituted at the N1 position with R¹⁹ where R¹⁹ is alkyl or alkenyl), imidazo[1,2-a]pyridin-5,6-diyl, cinnolin-6,7-diyl, quinolin-6,7-diyl, pyridin-3,4-diyl, 1-oxido-pyridin-3,4-diyl, [1,2,4]triazolo[4,3-a]pyridin-6,7-diyl, and 2,3-dihydroimidazo[1,2-a]pyridin-6,7-diyl.

In another embodiment of the Invention (B6), the compound of Formula I is selected from Group B where A is thien-diyl and X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, and R¹² are as defined in the Summary of the Invention for a compound of Group B.

In another embodiment A is thien-3,4-diyl; R¹⁰ and R¹² are hydrogen; X and R⁷ are halo; and R¹, R², R⁵, and R⁶ are hydrogen. In another embodiment, X is fluoro or chloro; R⁷ is iodo or bromo; R³ is hydrogen or hydroxy; and R⁴ is —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen or alkyl), heterocycloalkyl, heteroaryl (optionally substituted with alkyl), or alkyl where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl).

In another embodiment (B7), the compound of Formula I is more specifically according to Formula I(c) or I(d)

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹² and R¹⁴ are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰, R¹², and R¹⁴ are independently hydrogen, halo, or alkyl. In another embodiment, X is fluoro or chloro and R⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, in another embodiment hydrogen or fluoro; R¹² is hydrogen; R¹⁴ is hydrogen or alkyl; and R³ is hydroxy. In another embodiment, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B8), the compound of Formula I is more specifically according to Formula I(e) or I(f):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰, R¹², and R¹⁴ are independently hydrogen, halo, or alkyl. In another embodiment, X is fluoro or chloro and R⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, in another embodiment hydrogen or fluoro; R¹² and R¹⁴ are hydrogen; R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.

In another embodiment of the Invention (B9), the compound of Formula I is in another embodiment according to Formula I(g) or I(h):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹², R¹⁴, and R¹⁹ are as defined in the Summary of the Invention for a compound of Group B.

In another embodiment of embodiment B9, the compound of Formula I is more specifically according to Formula I(g) or I(h) where

-   R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,     —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),     —CH₂N(R²⁵)(NR^(25a)R^(25b)), CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN),     —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), cycloalkyl,     heteroaryl, or heterocycloalkyl; where the cycloalkyl, heteroaryl,     and heterocycloalkyl are optionally substituted with one, two,     three, four, five, six or seven groups independently selected from     halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl,     optionally substituted heterocycloalkyl, optionally substituted     aryl, optionally substituted arylalkyl, optionally substituted     heteroaryl, optionally substituted heteroarylalkyl, —OR⁸,     —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,     —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and     —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the     Invention; or R³ and R⁴ together with the carbon to which they are     attached form C(O) or C(═NOH); and     all other groups are as defined in the Summary of the Invention for     a compound of Group B.

In another embodiment of embodiment B9, the compound of Formula I is more specifically according to Formula I(g) or I(h) where R³ is hydroxy and all other groups are as defined in the Summary of the Invention for a compound of Group B.

In another embodiment of embodiment B9, the compound of Formula I is more specifically according to Formula I(g) or I(h) where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; R¹⁰, R¹², and R¹⁴ are independently hydrogen, halo, or alkyl; and R¹⁹ is hydrogen or methyl. In another embodiment, X is fluoro or chloro and R⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, in another embodiment hydrogen or fluoro; R¹² and R¹⁴ are hydrogen; R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.

In another embodiment of the Invention (B10), the compound of Formula I is more specifically according to Formula I(i) or I(j):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰, R¹², and R¹⁴ are independently hydrogen, halo, or alkyl. In another embodiment, X is fluoro or chloro and R⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, in another embodiment hydrogen or fluoro; R¹² and R¹⁴ are hydrogen; R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.

In another embodiment of the Invention (B11), the compound of Formula I is more specifically according to Formula I(k) or I(m):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰, R¹², and R¹⁴ are independently hydrogen, halo, or alkyl. In another embodiment, X is fluoro or chloro and R⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, in another embodiment hydrogen or fluoro; R¹² and R¹⁴ are hydrogen; R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.

In another embodiment of the Invention (B12), the compound of Formula I is more specifically according to Formula I(n) or I(o):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹², R¹⁴, and R¹⁹ are as defined in the Summary of the Invention for a compound of Group B.

In another embodiment of embodiment B12, the compound of Formula I is more specifically according to Formula I(n) or I(o) where R⁷ is halo or alkyl; and all other groups are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R⁷ is iodo or bromo.

In another embodiment of embodiment B12, the compound of Formula I is more specifically according to Formula I(n) or I(o) where X is halo, haloalkyl, or haloalkoxy; and all other groups are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, X is halo. In another embodiment X is fluoro or chloro.

In another embodiment of embodiment B12, the compound of Formula I is more specifically according to Formula I(n) or I(o) where

-   R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,     —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),     —CH₂N(R²⁵)(NR^(25a)R^(25b)), CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN),     —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,     alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where     the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and     heterocycloalkyl are independently optionally substituted with one,     two, three, four, five, six or seven groups independently selected     from halo, alkyl, haloalkyl, nitro, optionally substituted     cycloalkyl, optionally substituted heterocycloalkyl, optionally     substituted aryl, optionally substituted arylalkyl, optionally     substituted heteroaryl, optionally substituted heteroarylalkyl,     —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,     —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and     —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the     Invention; or -   R³ and R⁴ together with the carbon to which they are attached form     C(O) or C(═NOH); and     unless otherwise indicated, R⁸ and R^(8′) are as defined in the     Summary of the Invention; and all other groups are as defined in the     Summary of the Invention for a compound of Group B.

In another embodiment of embodiment B12, the compound of Formula I is more specifically according to Formula I(n) or I(o) where R¹⁹ is alkyl; R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰, R¹², and R¹⁴ are independently hydrogen or halo. In another embodiment, R¹⁹ is methyl; X is fluoro or chloro and R⁷ is iodo or bromo; R¹⁰ is hydrogen or fluoro; R¹² and R¹⁴ are hydrogen; and R³ is hydroxy. In another embodiment, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B13), the compound of Formula I is more specifically according to Formula I(p):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹², and R¹⁹ are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰ and R¹² are independently hydrogen, halo, or alkyl. In another embodiment, X is fluoro or chloro; R⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, in another embodiment hydrogen or fluoro; R¹² is hydrogen; R¹⁹ is hydrogen or alkyl, in another embodiment hydrogen or methyl; R³ is hydroxy. In another embodiment, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B14), the compound of Formula I is more specifically according to Formula I(q):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹², R¹⁴, and R¹⁶ areas defined in the Summary of the Invention for a compound of Group B.

In another embodiment of embodiment B14, the compound of Formula I is more specifically according to Formula I(q) where

-   R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,     —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),     —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),     —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN),     —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,     alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where     the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and     heterocycloalkyl are independently optionally substituted with one,     two, three, four, five, six or seven groups independently selected     from halo, alkyl, haloalkyl, nitro, optionally substituted     cycloalkyl, optionally substituted heterocycloalkyl, optionally     substituted aryl, optionally substituted arylalkyl, optionally     substituted heteroaryl, optionally substituted heteroarylalkyl,     —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,     —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and     —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the     Invention; or -   R³ and R⁴ together with the carbon to which they are attached form     C(O) or C(═NOH); and -   all other groups are as defined in the Summary of the Invention for     a compound of Group B.

In another embodiment of embodiment B14, the compound of Formula I is more specifically according to Formula I(q) where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰, R¹², R¹⁴, and R¹⁶ are independently hydrogen or halo. In another embodiment, R¹⁰ is halo and R¹², R¹⁴, and R¹⁶ are hydrogen. In another embodiment, X is fluoro or chloro; R⁷ is iodo or bromo; R¹⁰ is chloro; and R³ is hydroxy. In another embodiment, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, benzimidazolyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B15), the compound of Formula I is more specifically according to Formula I(r):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; R¹⁰ and R¹² are independently hydrogen, halo, or alkyl; and R¹⁴ is hydrogen, halo, alkyl, or amino. In another embodiment, X is fluoro or chloro; R⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, in another embodiment hydrogen or fluoro; R¹² is hydrogen; R¹⁴ is hydrogen, alkyl, or amino, in another embodiment hydrogen, methyl, or amino; R³ is hydroxy. In another embodiment, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B16), the compound of Formula I is more specifically according to Formula I(s):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰ and R¹² are independently hydrogen, halo, or alkyl; and R¹⁴ is hydrogen, halo, alkyl, or amino. In another embodiment, X is fluoro or chloro and R⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, in another embodiment hydrogen or fluoro; R¹² is hydrogen; R¹⁴ is hydrogen, methyl, or amino; R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.

In another embodiment of the Invention (B18), the compound of Formula I is more specifically according to Formula I(u), I(v), I(w), or I(x):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined in the Summary of the Invention for a compound of Group B.

In another embodiment of embodiment B18, the compound of Formula I is more specifically according to Formula I(u), I(v), I(w), or I(x) where R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the Invention for a compound of Group B; or R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group B.

In another embodiment of embodiment B18, the compound of Formula I is more specifically according to Formula I(t), I(u), I(v), or I(w) where R³ and R⁴ are independently halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR²⁵R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group B.

In another embodiment of embodiment B18, the compound of Formula I is more specifically according to Formula I(u), I(v), I(w), or I(x) where R⁴ is heterocycloalkyl, heteroaryl (optionally substituted with alkyl), or alkyl where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl). In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl.

In another embodiment of embodiment B18, the compound of Formula I is more specifically according to Formula I(u), I(v), I(w), or I(x) where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ and R⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰, R¹², and R¹⁴ are independently hydrogen, halo, or alkyl. In another embodiment, X is fluoro or chloro; R⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, in another embodiment hydrogen or fluoro; R¹² and R¹⁴ are hydrogen; and R³ is hydroxy. In another embodiment R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.

In another embodiment of the Invention (B19), the compound of Formula I is more specifically according to Formula I(cc)

where X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; and X and R⁷ are halo. In another embodiment, X is fluoro or chloro; and R³ is hydrogen or hydroxy; R⁷ is iodo or bromo. In another embodiment, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methyl-benzimidazolyl, methylaminomethyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl, 1(R,S)-(dimethylamino)-propyl, 1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In an embodiment (B19a) of embodiment B19, the compound of Formula I is that where R⁴ is heterocycloalkyl or alkyl where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl). In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, methylaminomethyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl, 1(R,S)-(dimethylamino)-propyl, 1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B20), the compound of Formula I is more specifically according to Formula I(dd)

where X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in the Summary of the Invention for a compound of Group B. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; and X and R⁷ are halo. In another embodiment, X is fluoro or chloro; and R³ is hydrogen or hydroxy; R⁷ is iodo or bromo. In another embodiment, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methyl-benzimidazolyl, methylaminomethyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl, 1(R,S)-(dimethylamino)-propyl, 1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In an embodiment (B20a) of embodiment B20, the compound of Formula I is that where R⁴ is heterocycloalkyl or alkyl where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl). In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, methylaminomethyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl, 1(R,S)-(dimethylamino)-propyl, 1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In one embodiment of the Invention (C1), the compound of Formula I is selected from Group C where all groups are as defined in the Summary of the Invention.

In another embodiment of the invention (C2), the compound of Formula I is that where X and R⁷ are halo; and all other groups are as defined for a compound selected from Group C.

In another embodiment of the invention (C3), the compound of Formula I is selected from Group C where R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)), CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the Invention; or R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group C. In another embodiment, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of the invention (C4), the compound of Formula I is selected from Group C where R³ and R⁴ are independently halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8″), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group C. In another embodiment, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of the invention (C5), the compound of Formula I is that where A is

and X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, and R^(10a) are as defined in the Summary of the invention for a compound of Group C. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R¹⁰ is hydrogen or halo; and R^(10a) is alkyl. In another embodiment, X is fluoro or chloro; R³ is hydroxy; R⁷ is iodo or bromo; R¹⁰ is hydrogen or fluoro; and R^(10a) is methyl. In another embodiment, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methyl-benzimidazolyl, methylaminomethyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl, 1(R,S)-(dimethylamino)-propyl, 1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the invention (C6), the compound of Formula I is that where A is

and X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, and R^(10a) are as defined in the Summary of the invention for a compound of Group C. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R¹⁰ is hydrogen or halo; and R^(10a) is alkyl. In another embodiment, X is fluoro or chloro; R³ is hydroxy; R⁷ is iodo or bromo; R¹⁰ is hydrogen or fluoro; and R^(10a) is methyl. In another embodiment, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methylbenzimidazolyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl, 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (C7), the compound of Formula I is more specifically of Formula I(y) or I(z):

where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³, R⁴, R¹⁰, R^(10a), and Y¹ are as defined in the Summary of the Invention for a compound of Group C. In another embodiment, X is fluoro or chloro; R⁷ is iodo or bromo; R¹⁰ is hydrogen, halo, or alkyl, in another embodiment hydrogen or halo; and R^(10a) is alkyl, in another embodiment methyl. In another embodiment R¹⁰ is hydrogen or fluoro; R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.

In one embodiment of the Invention (D), the compound of Formula I is selected from Group D where all groups are as defined in the Summary of the Invention.

In another embodiment of the invention (D1), the compound of Formula I is that where X and R⁷ are halo; and all other groups are as defined for a compound selected from Group D.

In another embodiment of the invention (D2), the compound of Formula I is selected from Group D where R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the Invention; or R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group C. In another embodiment, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of the invention (D3), the compound of Formula I is selected from Group D where R³ and R⁴ are independently halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8″), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group C. In another embodiment, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of the invention (D4), the compound of Formula I is that where A is

where R⁴⁰ is hydrogen or methyl (in another embodiment, R⁴⁰ is hydrogen) and all other groups are as defined in the Summary of the Invention. In another embodiment, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; and R⁴⁰ is hydrogen or methyl. In another embodiment, X is fluoro or chloro; and R³ is hydrogen or hydroxy; R⁷ is iodo or bromo. In another embodiment, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R⁸ is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methyl-benzimidazolyl, methylaminomethyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl, 1(R,S)-(dimethylamino)-propyl, 1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In an embodiment (D4a) of the invention of D4, the compound of Formula I is that where R⁴ is heterocycloalkyl or alkyl where the alkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl). In another embodiment, R⁴ is piperidinyl, pyrrolidinyl, methylaminomethyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl, 1(R,S)-(dimethylamino)-propyl, 1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl, 1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

Another embodiment of the Invention (E) is directed to a Compound of Formula I selected from Group A, Group B, and Group C where

Group A

-   A is phenylene optionally substituted with one or two groups     selected from R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴ and R¹⁶ are     independently hydrogen or halo; -   X is halo; -   R¹, R², R⁵ and R⁶ are hydrogen; -   R³ is hydrogen, halo, hydroxy, alkoxy, or amino; -   R⁴ is hydrogen, —NR⁸R^(8′), —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),     —NR⁸C(O)R^(8′), CH₂N(R²⁵)(NR^(25a)R^(25b)),     —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂),     —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵),     —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, cycloalkyl,     heterocycloalkyl, or heteroaryl; where the R⁴ alkyl is optionally     substituted with one, two, or three groups independently selected     from —OR⁸, halo, nitro, —S(O)_(m)R⁹, optionally substituted     heterocycloalkyl, —NR⁸R^(8′), —NR⁸C(O)R^(8′), —NR⁸S(O)₂R⁹,     —NR⁸C(O)OR^(8′), and aryl; where the R⁴ cycloalkyl is optionally     substituted with one or two groups selected from —OR⁸ and     —NR⁸R^(8′); where the R⁴ heterocycloalkyl is optionally substituted     with one or two groups independently selected from alkyl and     —C(O)OR⁸; and where the R⁴ heteroaryl is optionally substituted with     —NR⁸R^(8′); or -   R³ and R⁴ together with the carbon to which they are attached form     C(O) or C(═NOH); -   m is 0; -   R⁷ is halo; -   R⁸ and R^(8′) are independently selected from hydrogen, hydroxy,     alkyl, alkenyl, alkynyl, aryl, heterocycloalkyl, heteroaryl, and     cycloalkyl; -   where the R⁸ and R^(8′) alkyl are independently optionally     substituted with one, two, or three groups independently selected     from hydroxy, —NR³⁰R^(30′) (where R³⁰ and R^(30′) are independently     hydrogen, alkyl, or hydroxyalkyl), optionally substituted     heteroaryl, optionally substituted cycloalkyl), optionally     substituted alkoxy, optionally substituted cycloalkyl, optionally     substituted aryl, optionally substituted heterocycloalkyl,     optionally substituted heteroaryl, —C(O)NR³³R^(33a) (where R³³ is     hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or     cycloalkyl), optionally substituted aryloxy, —S(O)_(n)R³¹ (where n     is 0 and R³¹ is alkyl), carboxy, alkoxycarbonyl, and     —NR³²C(O)R^(32a) (where R³² is hydrogen or alkyl and R^(32a) is     alkyl, alkenyl, alkoxy, or cycloalkyl); or where the alkyl is     optionally substituted with one, two, three, four, or five halo; -   where the R⁸ and R^(8′) heteroaryl are independently optionally     substituted with one or two groups independently selected from amino     and alkyl; -   where the R⁸ and R^(8′) heterocycloalkyl are independently     optionally substituted with one, two, or three groups independently     selected from alkyl, alkoxycarbonyl, optionally substituted     arylalkyl, hydroxy, alkoxy, and hydroxyalkyl; -   where the R⁸ and R^(8′) aryl are independently optionally     substituted with one or two groups independently selected from     hydroxy, alkoxy, halo, —NR³²C(O)R^(32a) (where R³² is hydrogen or     alkyl and R^(32a) is alkyl, alkenyl, alkoxy, or cycloalkyl), and     —NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or alkyl and R^(34a) is     alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl);     and -   where the R⁸ and R^(8′) cycloalkyl are independently optionally     substituted with one, two, or three groups independently selected     from hydroxy, hydroxyalkyl, alkoxy, carboxy, —C(O)NR³³R^(33a) (where     R³³ is hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or     cycloalkyl), and optionally substituted cycloalkyl; and -   R⁹ is alkyl or aryl;     Group B -   A is thien-3,4-diyl, benzo[d]isoxazol-5,6-diyl, 1H-indazol-5,6-diyl     (optionally substituted at the N1 position with R¹⁹ where R¹⁹ is     alkyl or alkenyl), benzo[d]oxazol-5,6-diyl,     benzo[d]thiazol-5,6-diyl, 1H-benzo[d]imidazol-5,6-diyl (optionally     substituted at the N1 position with R¹⁹ where R¹⁹ is alkyl or     alkenyl), 1H-benzo[d][1,2,3]triazol-5,6-diyl (optionally substituted     at the N1 position with R¹⁹ where R¹⁹ is alkyl or alkenyl),     imidazo[1,2-a]pyridin-6,7-diyl, cinnolin-6,7-diyl,     quinolin-6,7-diyl, pyridin-3,4-diyl, or 1-oxido-pyridin-3,4-diyl;     where A is optionally substituted with one, two, or three groups     independently selected from R¹⁰, R¹², R¹⁴, R¹⁶ and R¹⁹ where R¹⁰,     R¹², R¹⁴ and R¹⁶ are independently hydrogen, alkyl, halo, or amino;     and R¹⁹ is hydrogen or alkyl; -   X is halo; -   R¹, R², R⁵ and R⁶ are hydrogen; -   R³ is hydrogen or hydroxy; -   R⁴ is —NR⁸R^(8′), heterocycloalkyl, heteroaryl, or alkyl; where the     alkyl is optionally substituted with —NR⁸R^(8′) and where the     heteroaryl is optionally substituted with alkyl; -   R⁷ is halo; -   R⁸ is hydrogen or alkyl; and -   R^(8′) is hydrogen, alkyl, or cycloalkyl; where the cycloalkyl is     optionally substituted with one or two groups independently selected     from hydroxy and alkyl;     Group C -   A is

-   where R¹⁰ is hydrogen or halo; -   R^(10a) is hydrogen or alkyl; -   Y¹ is ═CH— or ═N—; -   X is halo; -   R¹, R², R⁵ and R⁶ are hydrogen; -   R³ is hydrogen or hydroxy; -   R⁴ is —NR⁸R^(8′), heterocycloalkyl, heteroaryl, or alkyl; where the     alkyl is optionally substituted with —NR⁸R^(8′) and where the     heteroaryl is optionally substituted with alkyl; -   R⁷ is halo; -   R⁸ is hydrogen or alkyl; and -   R^(8′) is hydrogen, alkyl, or cycloalkyl; where the cycloalkyl is     optionally substituted with one or two groups independently selected     from hydroxy and alkyl.

Representative MEK Compounds

Representative compounds of Formula I are depicted below. The examples are merely illustrative and do not limit the scope of the invention in any way. Compounds of the invention are named according to systematic application of the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC), International Union of Biochemistry and Molecular Biology (IUBMB), and the Chemical Abstracts Service (CAS). Names were generated using ACD/Labs naming software 8.00 release, product version 8.08.

TABLE 1 Representative MEK Inhibitors Cmpd No. Structure Name 1

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}- carbonyl)azetidin-3-ol 2

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-one 3

6-(azetidin-1-ylcarbonyl)-2,3- difluoro-N-(2-fluoro-4- iodophenyl)aniline 4

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-(hydroxymethyl)azetidin-3-ol 5

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-(trifluoromethyl)azetidin-3-ol 6

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-prop-2-en-1-ylazetidin-3-ol 7

3-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]propane- 1,2-diol 8

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-ethylazetidin-3-ol 9

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-methylazetidin-3-ol 10

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-ethenylazetidin-3-ol 11

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-one oxime 12

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]methanol 13

1-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]ethane-1,2- diol 14

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 15

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- N-hydroxyazetidine-3-carboxamide 16

1,1-dimethylethyl[1-({3,4-difluoro- 2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]carbamate 17

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-(pyrrolidin-1-ylmethyl)azetidin-3- ol 18

3-[(diethylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 19

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-(dimethylamino)methyl]azetidin- 3-ol 20

N-butyl-1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidine-3-carboxamide 21

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- N-prop-2-en-1-ylazetidine-3- carboxamide 22

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]-2-methylpropanamide 23

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]formamide 24

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]-3,4- dihydroxybutanamide 25

methyl[1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]carbamate 26

N-butyl-1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 27

1-({4-[(2-fluoro-4- iodophenyl)amino]-3- thienyl}carbonyl)azetidin-3-amine 28

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-[(2S)-piperidin-2-yl]azetidin-3-ol 29

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-[(2R)-piperidin-2-yl]azetidin-3-ol 30

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-pyrrolidin-2-ylazetidin-3-ol 31

(R)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-pyrrolidin-2-ylazetidin-3-ol 32

(S)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-pyrrolidin-2-ylazetidin-3-ol 33

3-(aminomethyl)-1-({3,4-difluoro-2- [(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 34

3-[(1S)-1-aminomethyl]-1-({3,4-difluoro- 2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 35

3-[(1R)-1-aminomethyl]-1-({3,4-difluoro- 2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 36

(3-(1-aminopropyl)-3-hydroxyazetidin- 1-yl)(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)methanone 37

(R)-(3-(1-aminopropyl)-3- hydroxyazetidin-1-yl)(3,4-difluoro- 2-(2-fluoro-4- iodophenylamino)phenyl)methanone 38

(S)-(3-(1-aminopropyl)-3- hydroxyazetidin-1-yl)(3,4-difluoro- 2-(2-fluoro-4- iodophenylamino)phenyl)methanone 39

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- ethylazetidine-3-carboxamide 40

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- (2-hydroxyethyl)azetidine-3- carboxamide 41

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- (2-piperidin-1-ylethyl)azetidine-3- carboxamide 42

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- phenylazetidine-3-carboxamide 43

N-[2-(diethylamino)ethyl]-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidine-3-carboxamide 44

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (morpholin-4-ylmethyl)azetidin-3-ol 45

1-({1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-ylmethyl}piperidin- 4-ol 46

3-{[bis(2-hyroxyethyl)amino]methyl}- 1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 47

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]-2-(4-methylpiperazin-1- yl)acetamide 48

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(4-methylpiperazin-1- yl)methyl]azetidin-3-ol 49

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(4-methyl-1,4-diazepan-1- yl)methyl]azetidin-3-ol 50

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[methyl(1-methylpyrrolidin-3- yl)amino]methyl}azetidin-3-ol 51

3-(1,4′-bipiperidin-1′-ylmethyl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 52

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]-N,N-bis(2- hydroxyethyl)glycinamide 53

3-({4-[2-(diethylamino)ethyl]piperiazin- 1-yl}methyl)-1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 54

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2- hydroxyethyl)(methyl)amino]methyl} azetidin-3-ol 55

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]-2-piperidin-1-ylacetamide 56

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]-N3-(2-hydroxyethyl)-N3- methyl-beta-alaninamide 57

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]-N3,N3-bis(2-hydroxyethyl)- beta-alaninamide 58

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]-N2,N2-diethylglycinamide 59

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- methylazetidin-3-amine 60

1-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]-N,N-dimethylpyrrolidin-3- amine 61

2-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]amino}ethanol 62

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]propane-1,3-diamine 63

3-[(dimethylamino)methyl]-1-({4-[(2- fluoro-4-iodophenyl)amino]-3- thienyl}carbonyl)azetidin-3-ol 64

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- methyl-N-(2-pyridin-2-ylethyl)azetidin- 3-amine 65

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]-N2-methylglycinamide 66

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- ethylazetidin-3-amine 67

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- (2-methylpropyl)azetidin-3-amine 68

N-(cyclopropylmethyl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 69

N-(cyclohexylmethyl)-1-({3,4-difluoro- 2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 70

N-(cyclopentylmethyl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 71

3-(azetidin-1-ylmethyl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 72

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- [(2,3-dihydroxypropyl)oxy]azetidine-3- carboxamide 73

2-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-2-yl]methyl}amino)ethanol 74

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-2-yl]-methyl}ethane-1,2-diamine 75

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]glycinamide 76

6-({3-[(dimethylamino)methyl]azetidin- 1-yl}carbonyl)-2,3-difluoro-N-(2- fluoro-4-iodophenyl)aniline 77

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1- methylethyl)amino]methyl}azetidin-3-ol 78

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- (3,4-dihydroxybutyl)azetidine-3- carboxamide 79

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- (2,3-dihydroxypropyl)azetidine-3- carboxamide 80

1-({2,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 81

1-({4,5-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 82

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidine-3-carboxamide 83

6-{[3-(aminomethyl)-3- (methyloxy)azetidin-1-yl]carbonyl}- 2,3-difluoro-N-(2-fluoro-4- iodophenyl)aniline 84

N-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}acetamide 85

2,3-difluoro-N-(2-fluoro-4-iodophenyl)- 6-[3-{[(1- methylethyl)amino]methyl}azetidin-1- yl)carbonyl]aniline 86

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(ethylamino)methyl]azetidin-3-ol 87

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {2-[(1- methylethyl)amino]ethyl}azetidin-3-ol 88

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (2-hydroxy-1,1-dimethylethyl)azetidin- 3-ol 89

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {1,1-dimethyl-2-[(1- methylethyl)amino]ethyl}azetidin-3-ol 90

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1- methylethyl)amino]ethyl}azetidin-3- amine 91

3-[(cyclopropylamino)methyl]-1- ({3,4-difluoro-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 92

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2,2,2- trifluoroethyl)amino]methyl}azetidin-3- ol 93

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1H-imidazol-1-ylmethyl)azetidin-3-ol 94

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1- dimethylethyl)amino]methyl}azetidin- 3-ol 95

3-[(cyclopentylamino)methyl]-1- ({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 96

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxy-N-prop-2-en-1-ylazetidine-3- carboxamide 97

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N- (2,3-dihydroxypropyl)-3- hydroxyazetidine-3-carboxamide 98

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1H-1,2,3-triazol-1-ylmethyl)azetidin- 3-ol 99

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2,2- dimethylpropyl)amino]methyl}azetidin- 3-ol 100

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(propylamino)methyl]azetidin-3-ol 101

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-{[(2- methylpropyl)amino]methyl}azetidin- 3-ol 102

3-{[(cyclopropylmethyl)amino]methyl}- 1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 103

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(phenylmethyl)amino]methyl}azetidin- 3-ol 104

3-{[(cyclohexylmethyl)amino]methyl}- 1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 105

3-[(butylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 106

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(1-ethylpyrrolidin)-2- yl)methyl]amino}methyl)azetidin-3-ol 107

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(2- hydroxyethyl)amino]methyl}azetidin-3-ol 108

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(2- (dimethylamino)ethyl]amino}methyl) azetidin-3-ol 109

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2-hydroxy-1,1- dimethylethyl)amino]methyl}azetidin-3-ol 110

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(4- methylphenyl)ethyl]amino}methyl) azetidin-3-ol 111

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(prop-2-en-1-ylamino)methyl]azetidin-3-ol 112

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(1-methylpyrrolidin-2- yl)ethyl]amino}methyl)azetidin-3-ol 113

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(2,3-dihydro-1H-inden-2- ylamino)methyl]azetidin-3-ol 114

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(tetrahydrofuran-2- ylmethyl)amino]methyl}azetidin-3-ol 115

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(tetrahydro-2H-pyran-4- yl)ethyl]amino}methyl)azetidin-3-ol 116

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(1S,2S)-2- hydroxycyclopentyl]amino}methyl) azetidin-3-ol 117

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1-dimethylprop-2-yn-1- yl)amino]methyl}azetidin-3-ol 118

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(3-pyrrolidin-1- ylpropyl)amino]methyl}azetidin-3-ol 119

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1,2- dimethylpropyl)amino]methyl}azetidin-3-ol 120

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(1H-imidazol-4- yl)ethyl]amino}methyl)azetidin-3-ol 121

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[1-methyl-2- (methyloxy)ethyl]amino}methyl) azetidin-3-ol 122

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[3- (ethyloxy)propyl]amino}methyl) azetidin-3-ol 123

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[1- ethylpropyl)amino]methyl}azetidin-3-ol 124

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[3,3- dimethylbutyl)amino]methyl} azetidin-3-ol 125

ethyl 4-({[1-({3,4-difluoro-2-[(2-fluoro- 4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3- yl]methyl}amino)piperidine-1- carboxylate 126

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(3- methylbutyl)amino]methyl}azetidin-3-ol 127

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2- (ethyloxy)ethyl]amino}methyl)azetidin- 3-ol 128

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[3- (dimethylamino)propyl]amino}methyl) azetidin-3-ol 129

3-[(cyclobutylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 130

3-({[3- (diethylamino)propyl]amino}methyl)-1- ({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 131

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[3-(1H-imidazol-1- yl)propyl]amino}methyl)azetidin-3-ol 132

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2- (methylthio)ethyl]amino}methyl) azetidin-3-ol 133

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[1-(phenylmethyl)piperidin-4- yl]amino}methyl)azetidin-3-ol 134

3-({[2,2- bis(methyloxy)ethyl]amino}methyl)-1- ({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 135

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1,3,3- tetramethylbutyl)amino]methyl} azetidin-3-ol 136

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1- dimethylpropyl)amino]methyl}azetidin- 3-ol 137

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(2,3-dihydro-1H-inden-1- ylamino)methyl]azetidin-3-ol 138

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [({2- [(phenylmethyl)oxy]cyclopentyl}amino) methyl]azetidin-3-ol 139

3-{[(3-amino-2- hydroxypropyl)amino]methyl}-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 140

({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2-hydroxy-1- (phenylmethyl)ethyl]amino}methyl) azetidin-3-ol 141

3-[(cyclooctylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 142

3-{[(1-cyclohexylethyl)amino]methyl}- 1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 143

3-[(cycloheptylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 144

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2-pyridin-3- ylethyl)amino]methyl}azetidin-3-ol 145

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[3- (methylthio)propyl]amino}methyl) azetidin-3-ol 146

N-cyclohexyl-N~2~-{[1-({3,4-difluoro- 2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}-2- methylalaninamide 147

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(tetrahydro-2H-pyran-4- ylmethyl)amino]methyl}azetidin-3-ol 148

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(3- hydroxypropyl)amino]methyl} azetidin-3-ol 149

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2-pyridin-4- ylethyl)amino]methyl}azetidin-3-ol 150

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[1-(phenylmethyl)pyrrolidin-3- yl]amino}methyl)azetidin-3-ol 151

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(2- thienyl)ethyl]amino}methyl)azetidin-3-ol 152

3-[({2-[bis(1- methylethyl)amino]ethyl}amino)methyl]- 1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 153

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2- (phenyloxy)ethyl]amino}methyl) azetidin-3-ol 154

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(phenylamino)methyl]azetidin-3-ol 155

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2- hydroxypropyl)amino]methyl}azetidin- 3-ol 156

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [({2-[(1- methylethyl)oxy]ethyl}amino)methyl] azetidin-3-ol 157

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1-ethylpiperidin-3- yl)amino]methyl}azetidin-3-ol 158

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2- (methyloxy)ethyl]amino}methyl)azetidin- 3-ol 159

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1-nitropropyl)azetidin-3-ol 160

3-(1-aminoethyl)-1-({3,4-difluoro-2- [(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 161

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(1-methylpiperidin-4- yl)methyl]amino}methyl)azetidin-3-ol 162

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[4- (dimethylamino)butyl]amino}methyl) azetidin-3-ol 163

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2-furan-2- ylethyl)amino]methyl}azetidin-3-ol 164

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1- dimethylethyl)amino]ethyl}azetidin-3-ol 165

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2-ethylbutyl)amino]methyl}azetidin- 3-ol 166

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}pyrrolidin-3-ol 167

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({(2S)-2- [(methyloxy)methyl]pyrrolidin-1- yl}methyl)azetidin-3-ol 168

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2- hydroxyphenyl)amino]methyl}azetidin- 3-ol 169

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(4- hydroxyphenyl)amino]methyl}azetidin- 3-ol 170

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(3- hydroxyphenyl)amino]methyl}azetidin- 3-ol 171

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(phenyloxy)methyl]azetidin-3-ol 172

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1r,3r,5R,7R)-tricyclo[3.3.1.1^(3,7)]dec- 2-ylamino]methyl}azetidin-3-ol 173

3-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}amino)propane-1,2-diol 174

N-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}-L- alanine 175

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(phenylthio)methyl]azetidin-3-ol 176

N-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}-D- alanine 177

methyl N-{[1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}alaninate 178

3-[({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}amino)oxy]propane-1,2-diol 179

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(5-methyl-1,3,4-oxadiazol-2- yl)methyl]amino}methyl)azetidin-3-ol 180

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1- methylbutyl)amino]methyl}azetidin-3-ol 181

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1- methylpropyl)amino]methyl}azetidin-3-ol 182

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2- methylbutyl)amino]methyl}azetidin-3-ol 183

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(pentylamino)methyl]azetidin-3-ol 184

3-[(1S)-1-aminoethyl]-1-({8-fluoro- 7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)azetidin-3-ol 185

1-({8-fluoro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)-3-[(1S)-1- (methylamino)ethyl]azetidin-3-ol 186

3-[(cyclohexylamino)methyl]-1-({3,4- difluoro-[2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 187

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [1-(ethylamino)ethyl]azetidin-3-ol 188

3-[(azepan-3-ylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 189

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(dimethylamino)-1- methylethyl]amino}methyl)azetidin-3-ol 190

N-cyclopropyl-1-({[1-({3,4-difluoro-2- [(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}amino)cyclopentanecarboxamide 191

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(2,3-dihydro-1H-indol-3- yl)ethyl]amino}methyl)azetidin-3-ol 192

N~2~-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}-N-ethyl- 2-methylalaninamide 193

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(2-methylhydrazino)methyl]azetidin-3-ol 194

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(hydroxyamino)methyl]azetidin-3-ol 195

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(methyloxy)amino]methyl}azetidin-3-ol 196

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(ethyloxy)amino]methyl}azetidin-3-ol 197

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [1-(ethylamino)propyl]azetidin-3-ol 198

3-[(azetidin-3-ylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 199

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(1,3-thiazol-2- ylamino)methyl]azetidin-3-ol 200

3-(1H-benzimidazol-2-yl)-1-({8- fluoro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)azetidin-3-ol 201

3-(1H-benzimidaZol-2-yl)-1-({7-[(4- bromo-2-fluorophenyl)amino]-8- fluoroimidazo[1,2-a]pyridin-6- yl}carbonyl)azetidin-3-ol 202

1,1-dimethylethyl [3-({[1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}amino)propyl]carbamate 203

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(pyrrolidin-2- ylmethyl)amino]methyl}azetidin-3-ol 204

1,1-dimethylethyl 4-[({[1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}amino)methyl]piperidine-1- carboxylate 205

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(2- hydroxyphenyl)methyl]amino}methyl) azetidin-3-ol 206

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(3- hydroxyphenyl)methyl]amino}methyl) azetidin-3-ol 207

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(4- hydroxyphenyl)methyl]amino}methyl) azetidin-3-ol 208

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(4- hydroxybutyl)amino]methyl} azetidin-3-ol 209

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(2- hydroxyethyl)oxy]methyl} azetidin-3-ol 210

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(1S,2S)-2- hydroxycyclohexyl]amino}methyl) azetidin-3-ol 211

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1-dimethyl-2-pyrrolidin-1- ylethyl)amino]methyl}azetidin-3-ol 212

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1-methyl-1H-imidazol-4- yl)methyl]amino}methyl)azetidin-3-ol 213

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(1-methyl-1H-imidazol-5- yl)methyl]amino}methyl)azetidin-3-ol 214

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(2S)-2- (methyloxy)cyclopentyl]amino}methyl) azetidin-3-ol 215

3-{[1,1′-bi(cyclohexyl)-2- ylamino]methyl}-1-({3,4-difluoro-2- [(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 216

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(3- (methyloxy)phenyl]amino}methyl) azetidin-3-ol 217

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}amino)cyclopentanecarboxylic acid 218

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(4- fluorophenyl)amino]methyl}azetidin-3-ol 219

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(1,3,5-triazin-2- ylamino)methyl]azetidin-3-ol 220

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(trans-4- hydroxycyclohexyl)amino]methyl} azetidin-3-ol 221

3-[(cyclopent-3-en-1-ylamino)methyl]- 1-({3,4-difluoro-2-[(2-f1uoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 222

N-[4-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}amino)phenyl]acetamide 223

N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}amino)phenyl]acetamide 224

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1-methylpyrrolidin-2-yl)azetidin-3-ol 225

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(1H-1,2,4-triazol-3- ylamino)methyl]azetidin-3-ol 226

3-[1-(diethylamino)propyl]-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 227

3-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)-5- (hydroxymethyl)cyclopentane-1,2-diol 228

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- piperidin-2-ylazetidin-3-ol 229

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[(3- fluorophenyl)amino]methyl}azetidin-3-ol 230

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1-methylpiperidin-2-yl)azetidin-3-ol 231

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}guanidine 232

1-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}-3- nitroguanidine 233

N-{1-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]ethyl}acetamide 234

(2R)-N-{1-[1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]ethyl}-3,3,3- trifluoro-2-(methyloxy)-2- phenylpropanamide 235

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(piperidin-4- ylmethyl)amino]methyl}azetidin-3-ol 236

3-{[(3-aminopropyl)amino]methyl}-1- ({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 237

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [({[2-(4-methylpiperazin-1- yl)phenyl]methyl}amino)methyl] azetidin-3-ol 238

3-{[(1,1-dimethylethyl)amino]methyl}- 1-({4-[(2-fluoro-4-iodophenyl)amino]- 3-thienyl}carbonyl)azetidin-3-ol 239

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2- hydroxycyclohexyl)amino]methyl} azetidin-3-ol 240

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2,2,3,3,3- pentafluoropropyl)amino]methyl}azetidin-3-ol 241

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(3,3,3,- trifluoropropyl)amino]methyl}azetidin- 3-ol 242

N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}caronyl)-3- hydroxyazetidin-3- yl]methyl}amino)phenyl]methanesulfonamide 243

N-{[1-({3,4-difluoro-2-[2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}methanesulfonamide 244

3-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)- 1H-pyrazol-5-ol 245

(1R,2S)-4-({[1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}amino)cyclopentane-1,2-diol 246

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[1-(hydroxymethyl)cyclohexyl]amino} methyl)azetidin-3-ol 247

3-{[(3-chlorophenyl)amino]methyl}-1- ({3,4-difluoro-2-[2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 248

3-{[(4-chlorophenyl)amino]methyl}-1- ({3,4-difluoro-2-[2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 249

3-[(5-amino-3-methyl-1H-pyrazol- yl)methyl]-1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 250

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(5-methyl-1H-pyrazol-3- yl)amino]methyl}azetidin-3-ol 251

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1-ethylpyrrolidin-2-yl)azetidin-3-ol 252

(2R)-N-{(1S)-1-[1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]ethyl}-3,3,3- trifluoro-2-(methyloxy)-2- phenylpropanamide 253

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[4- (methyloxy)phenyl]amino}methyl) azetidin-3-ol 254

3-(1-amino-2-methylpropyl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 255

3-{[(4-aminophenyl)amino]methyl}-1- ({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 256

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2-hydroxy-2- methylcyclopentyl)amino]methyl} azetidin-3-ol 257

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {1-[(4- hydroxycyclohexyl)amino]ethyl} azetidin-3-ol 258

methyl (2xi)-2-deoxy-2-({[1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)- beta-D-arabino-hexopyranoside 259

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- pyridin-2-ylazetidin-3-ol 260

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- ({[1- hydroxymethyl)cyclopentyl]amino} methyl)azetidin-3-ol 261

1-cyano-3-{[1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}guanidine 262

6-({3-[(ethylamino)methyl]-3- fluoroazetidin-1-yl}carbonyl)-2,3- difluoro-N-(2-fluoro-4- iodophenyl)aniline 263

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1-nitroethyl)azetidin-3-ol 264

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(3-fluoro-4- hydroxyphenyl)amino]methyl}azetidin- 3-ol 265

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- {[(2-fluoro-4- hydroxyphenyl)amino]methyl}azetidin- 3-ol 266

3-(1-aminoethyl)-1-({8-chloro-7-[(2- fluoro-4- iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)azetidin-3-ol 267

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [1-(methylamino)ethyl]azetidin-3-ol 268

1-({8-fluoro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)-3-[(2S)- piperidin-2-yl]azetidin-3-ol 269

1-({8-fluoro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)-3-{(1S)-1- [(2-hydroxy-2- methylcyclopentyl)amino]ethyl} azetidin-3-ol 270

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1H-imidazol-2-yl)azetidin-3-ol 271

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1H-pyrrol-2-yl)azetidin-3-ol 272

N-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3- yl]methyl}benzenecarboximidamide 273

3-({[(E)-1-amino-2- nitroethenyl]amino}methyl)1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 274

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1-methyl-1-nitroethyl)azetidin-3-ol 275

3-(1-amino-1-methylethyl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 276

3-[(1H-benzimidazol-2- ylamino)methyl]-1-({3,4-difluoro-2- [(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 277

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(1H-imidazol-2- ylamino)methyl]azetidin-3-ol 278

methyl {1-[1-({3,4-difluoro-2-[(2- fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]ethyl}carbamate 279

3-(1H-benzimidazol-2-yl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 280

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [1-(dimethylamino)ethyl]azetidin-3-ol 281

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(pyrimidin-2-ylamino)methyl]azetidin- 3-ol 282

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(pyridin-2-ylamino)methyl]azetidin-3-ol 283

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1-methyl-1H-imidazol-2-yl)azetidin-3-ol 284

3-(1-aminobutyl)-1-({3,4-difluoro-2- [(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 285

1-({2-fluoro-3-[2-fluoro-4- iodophenyl)amino]pyridin-4- yl}carbonyl)-3-[(2S)-pyrrolidin-2- yl]azetidin-3-ol 286

1-({8-fluoro-7-[(2-fluoro-4- iodophenyl)amino]-4- methylcinnolin-6-yl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol 287

3-[amino(phenyl)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 288

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (5-methyl-1H-imidazol-2-yl)azetidin-3-ol 289

1,1-dimethylethyl (2S)-2-[1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]piperidine-1- carboxylate 290

1-({2-[(4-bromo-2- chlorophenyl)amino]-3,4- difluorophenyl}carbonyl)-3-piperidin- 2-ylazetidin-3-ol 291

3-(1-amino-3-hydroxypropyl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 292

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (1H-imidazo1-2-ylmethyl)azetidin-3-ol 293

3-(1-aminocyclopentyl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 294

3-(2-aminocyclohexyl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 295

3-(2-aminocyclopentyl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- azetidin-3-ol 296

1-({4-fluoro-5-[(2-fluoro-4- iodophenyl)amino]-1-methyl-1H- benzimidazol-6-yl}carbonyl)-3- piperidin-2-ylazetidin-3-ol 297

1-({5-[(4-bromo-2- chlorophenyl)amino]-4-fluoro-1- methyl-1H-benzimidazol-6- yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 298

1-({8-chloro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)-3-piperidin-2- ylazetidin-3-ol 299

1-({2-[(4-bromo-2- fluorophenyl)amino]-3,4- difluorophenyl}carbonyl)-3-piperidin- 2-ylazetidin-3-ol 300

1-({7-[(4-bromo-2- fluorophenyl)amino]-8- fluoroimidazo[1,2-a]pyridin-6- yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 301

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (3-methyl-1-nitrobutyl)azetidin-3-ol 302

3-(2-aminopyrimidin-4-yl)-1-({3,4- difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 303

1-({7-[(4-bromo-2- chlorophenyl)amino]-8- chloroimidazo[1,2-a]pyridin-6- yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol 304

1-({8-chloro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)-3-[(2S)- piperidin-2-yl]azetidin-3-ol 305

1-({7-[(4-bromo-2- chlorophenyl)amino]-8- chloroimidazo[1,2-a]pyridin-6- yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 306

1--({4-fluoro-5-[(2-fluoro-4- iodophenyl)amino]-1-methyl-1H- benzimidazol-6-yl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol 307

3-[(1S)-1-aminoethyl]-1-({5-[(4- bromo-2-chlorophenyl)amino]-4- fluoro-1-methyl-1H-benzimidazol-6- yl}carbonyl)azetidin-3-ol 308

1-({5-[(4-bromo-2- chlorophenyl)amino]-4-fluoro-1- methyl-1H-benzimidazol-6- yl}carbonyl)-3-[(1S)-1- (methylamino)ethyl]azetidin-3-ol 309

4-[(4-bromo-2-fluorophenyl)amino]- 3-fluoro-5-({3-hydroxy-3-[(2S)- piperidin-2-yl]azetidin-1- yl}carbonyl)pyridin-2(1H)-one 310

4-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(2S)-piperidin-2- yl]azetidin-1-yl}carbonyl)-1- methylpyridin-2(1H)-one 311

4-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(2S)-piperidin-2- yl]azetidin-1-yl}carbonyl)-1- methylpyridin-2(1H)-one 312

(±)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(trans)-2-hydroxycyclohexyl]azetidin- 3-ol 313

(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)(3-hydroxy-3- ((1S,2S)-2-hydroxycyclohexyl)azetidin- 1-yl)methanone 314

(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)(3-hydroxy-3- ((1S,2R)-2-hydroxycyclohexyl)azetidin- 1-yl)methanone 315

4-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(1S)-1- (methylamino)propyl]azetidin-1- yl}carbonyl)-1-methylpyridin-2(1H)- one 316

(±)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(cis)-2-hydroxycyclohexyl]azetidin- 3-ol 317

(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)(3-hydroxy-3- ((1S,2R)-2-hydroxycyclohexyl)azetidin- 1-yl)methanone 318

(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)(3-hydroxy-3- ((1S,2S)-2-hydroxycyclohexyl)azetidin- 1-yl)methanone 319

5-({3-[(1S)-1- (dimethylamino)ethyl]-3- hydroxyazetidin-1-yl}carbonyl)-4- [(2-fluoro-4-iodophenyl)amino]-1- methylpyridin-2(1H)-one 320

4-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3- [(methylamino)methyl]azetidin-1- yl}carbonyl)-1-methylpyridin-2(1H)- one 321

5-{[3-(1H-benzimidazol-2-yl)-3- hydroxyazetidin-1-yl]carbonyl}-4- [(4-bromo-2-fluorophenyl)amino]-1- methylpyridin-2(1H)-one 322

4-[(4-bromo-2-fluorophenyl)amino]- 5-{[3-hydroxy-3-(1-methyl-1H- benzimidazol-2-yl)azetidin-1- yl]carbonyl}-1-methylpyridin-2(1H)- one 323

4-[(4-bromo-2-fluorophenyl)amino]- 5-({3-hydroxy-3-(2S)-pyrrolidin-2- yl]azetidin-1-yl}carbonyl)-1- methylpyridin-2(1H)-one 324

1-({3-fluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-[(2S)-piperidin-2-yl]azetidin-3-ol 325

1-({4-fluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)- 3-[(2S)-piperidin-2-yl]azetidin-3-ol 326

1-({6-[(4-bromo-2- chlorophenyl)amino]-7-fluoro-3- methyl-1,2-benzisoxazol-5- yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 327

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- (6-methylpiperidin-2-yl)azetidin- 3-ol 328

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- piperazin-2-ylazetidin-3-ol 329

5-[2-fluoro-4-iodophenyl)amino]-6- ({3-hydroxy-3-[(2S)-piperidin-2- yl]azetidin-1-yl}carbonyl)-2- methylpyridazin-3(2H)-one 330

5-[(4-bromo-2-chlorophenyl)amino]- 6-({3-hydroxy-3-[(2S)-piperidin-2- yl]azetidin-1-yl}carbonyl)-2- methylpyridazin-3(2H)-one 331

5-[(4-bromo-2-chlorophenyl)amino]- 4-fluoro-6-({3-hydroxy-3-[(2S)- pyrrolidin-2-yl]azetidin-1- yl}carbonyl)-2-methylpyridazin- 3(2H)-one 332

5-[(4-bromo-2-chlorophenyl)amino]- 4-fluoro-6-({3-hydroxy-3-[(2R)- pyrrolidin-2-yl]azetidin-1- yl}carbonyl)-2-methylpyridazin- 3(2H)-one 333

6-({3-[(1S)-1-aminoethyl]-3- hydroxyazetidin-1-yl}carbonyl)-5- [(2-fluoro-4-iodophenyl)amino]-2- methylpyridazin-3(2H)-one 334

6-({3-[(1S)-1-aminoethyl]-3- hydroxyazetidin-1-yl}carbonyl)-5- [(4-bromo-2-chlorophenyl)amino]-2- methylpyridazin-3(2H)-one 335

5-[(4-bromo-2-chlorophenyl)amino]- 6-{[3-((1S)-1-{[(3R,4S)-3,4- dihydroxycyclopentyl]amino}ethyl)- 3-hydroxyazetidin-1-yl]carbonyl}-2- methylpyridazin-3(2H)-one 336

5-[(4-bromo-2-fluorophenyl)amino]- 6-[(3-hydroxy-3-{(1S)-1-[(2- hydroxy-2- methylcyclopentyl)amino]propyl} azetidin-1-yl)carbonyl]-2- methylpyridazin-3(2H)-one 337

6-({3-[(1S)-1-aminopropyl]-3- hydroxyazetidin-1-yl}carbonyl)-5- [(4-bromo-2-fluorophenyl)amino]-2- methylpyridazin-3(2H)-one 338

6-{[3-(1H-benzimidazol-2-yl)-3- hydroxyazetidin-1-yl]carbonyl}-5- [(2-fluoro-4-iodophenyl)amino]-2- methylpyridazin-3(2H)-one 339

5-[(2-fluoro-4-iodophenyl)amino]-6- {[3-hydroxy-3-(1-methyl-1H- benzimidazol-2-yl)azetidin-1- yl]carbonyl}-2-methylpyridazin- 3(2H)-one 340

1-({2-fluoro-3-[(2-fluoro-4- iodophenyl)amino]pyridin-4- yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 341

1-({3-[(2-fluoro-4- iodophenyl)amino]pyridin-4- yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 342

1-({3-[(2-fluoro-4- iodophenyl)amino]-1-oxidopyridin- 4-yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 343

1-({2-fluoro-3-[(2-fluoro-4- bromophenyl)amino]pyridin-4- yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 344

3-[(1S)-1-aminopropyl]-1-({3-[(2- fluoro-4-iodophenyl)amino]pyridin- 4-yl}carbonyl)azetidin-3-ol 345

1-({3-[(2-fluoro-4- iodophenyl)amino]pyridin-4- yl}carbonyl)-3-[(1S)-1- (methylamino)propyl]azetidin-3-ol 346

(1R,2S)-4-({(1S)-1-[1-({2-fluoro-3- [2-fluoro-4- iodophenyl)amino]pyridin-4- yl}carbonyl)-3-hydroxyazetidin-3- yl]propyl}amino)cyclopentane-1,2- diol 347

1-({7-[(4-bromo-2- chlorophenyl)amino]-8-fluoro-4- methylcinnolin-6-yl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol 348

1-({7-[(4-bromo-2- fluorophenyl)amino]-8-fluoro-4- methylcinnolin-6-yl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol 349

3-[(1S)-1-aminoethyl]-1-({7-[(4- bromo-2- fluorophenyl)amino]cinnolin-6- yl}carbonyl)azetidin-3-ol 350

1-({7-[(4-bromo-2- fluorophenyl)amino]cinnolin-6- yl}carbonyl)-3-{(1S)-1-[(2-hydroxy- 2- methylcyclopentyl)amino]ethyl} azetidin-3-ol 351

1-({7-[(4-bromo-2- fluorophenyl)amino]cinnolin-6- yl}carbonyl)-3-[(1S)-1- (dimethylamino)ethyl]azetidin-3-ol 352

3-[(1S)-1-aminoethyl]-1-({5-[(2- fluoro-4-iodophenyl)amino]-1H- 1,2,3-benzotriazol-6- yl}carbonyl)azetidin-3-ol 353

3-[(1S)-1-(dimethylamino)ethyl]-1- ({5-[(2-fluoro-4-iodophenyl)amino]- 1-methyl-1H-1,2,3-benzotriazol-6- yl}carbonyl)azetidin-3-ol 354

1-({5-[(2-fluoro-4- iodophenyl)amino]-1H-1,2,3- benzotriazol-6-yl}carbonyl)-3-[(2S)- piperidin-2-yl]azetidin-3-ol 355

1-({5-[(2-fluoro-4- iodophenyl)amino]-1-methyl-1H- 1,2,3-benzotriazol-6-yl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol 356

1-({5-[(2-fluoro-4- iodophenyl)amino]-1H-1,2,3- benzotriazol-6-yl}carbonyl)-3-{(1S)- 1-[(2-hydroxy-2- methylcyclopentyl)amino]ethyl} azetidin-3-ol 357

3-[(1S)-1-aminoethyl]-1-({4-fluoro- 5-[(2-fluoro-4-iodophenyl)amino]- 1H-1,2,3-benzotriazol-6- yl}carbonyl)azetidin-3-ol 358

1-({4-fluoro-5-[(2-fluoro-4- iodophenyl)amino]-1H-1,2,3- benzotriazol-6-yl}carbonyl)-3-[(2S)- piperidin-2-yl]azetidin-3-ol 359

5-({3-[(1S)-1-aminoethyl]-3- hydroxyazetidin-1-yl}carbonyl)-6- [(2-fluoro-4- iodophenyl)amino]pyrimidin-2(1H)- one 360

6-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(2S)-piperidin-2- yl]azetidin-1-yl}carbonyl)pyrimidin- 2(1H)-one 361

4-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(2S)-piperidin-2- yl]azetidin-1-yl}carbonyl)pyrimidin- 2(1H)-one 362

5-({3-[(1S)-1-aminoethyl]-3- hydroxyazetidin-1-yl}carbonyl)-4- [(2-fluoro-4- iodophenyl)amino]pyrimidin-2(1H)- one

Other Representative Compounds

TABLE 2a Representative AKT Inhibitors Cmpd No. Name 1 3-(azetidin-3-ylidenemethyl)-4-[4-(5-chloro-2-methyl- phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 2 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3- fluoropyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine 3 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3- chloropyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine 4 2-({5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl) piperazin-1-yl]-2-methylphenyl}oxy)-N,N-dimethylethanamine 5 2-({5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl) piperazin-1-yl]-2-methylphenyl}oxy)-N,N-diethylethanamine 6 4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phen- yl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 7 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-piperazin-1-yl- 1H-pyrazolo[3,4-d]pyrimidine 8 N-(3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}prop-2-yn-1-yl)acetamide 9 N,N-diethyl-2-({3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]phenyl}oxy)ethanamine 10 3-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-5-chloro-2-methylphenyl}-N,N-diethylpropan-1-amine 11 3-bromo-4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1- ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 12 3-bromo-4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-yleth- yl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 13 2-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-5-chloro-2-methylphenyl}oxy)-N,N-diethylethanamine 14 4-[4-(5-chloro-2-methyl-3-{[2-(1-methylpiperidin-4- yl)ethyl]oxy}phenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine 15 5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl) piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 16 4-(4-{5-chloro-2-methyl-3-[(2-morpholin-4-ylethyl)oxy]phen- yl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 17 4-(4-{5-chloro-2-methyl-3-[(2-piperidin-1-ylethyl)oxy]phen- yl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 18 3-bromo-4-{4-[5-chloro-2-methyl-3-(3-morpholin-4-ylpropyl) phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 19 3-bromo-4-(4-{5-chloro-2-methyl-3-[3-(4-methylpiperazin-1-yl) propyl]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 20 3-bromo-4-(4-{5-chloro-2-methyl-3-[(2-piperidin-1-ylethyl)oxy] phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 21 3-bromo-4-(4-{5-chloro-2-methyl-3-[(2-morpholin-4-ylethyl) oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 22 4-{4-[5-chloro-2-methyl-3-(3-morpholin-4-ylpropyl)phen- yl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 23 N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methylphenyl}-N,N-diethylethane-1,2- diamine 24 4-{4-[5-chloro-2-methyl-3-(3-piperidin-1-ylpropyl)phen- yl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 25 4-[4-(5-chloro-3-{[2-(4-ethylpiperazin-1-yl)ethyl]oxy}-2- methylphenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine 26 4-(4-{5-chloro-2-methyl-3-[(3-morpholin-4-ylpropyl)oxy]phen- yl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 27 3-bromo-4-{4-[5-chloro-2-methyl-3-(3-piperidin-1- ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 28 N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-5-chloro-2-methylphenyl}-N,N-diethylethane-1,2-diamine 29 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-chloro-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 30 4-[4-(5-chloro-2-methyl-3-{[2-(4-methylpiperazin-1- yl)ethyl]oxy}phenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine 31 4-[4-(5-chloro-2-methyl-3-{[(1-methylpiperidin-4- yl)methyl]oxy}phenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine 32 N,N-diethyl-2-({3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methylphenyl}oxy)ethanamine 33 2-[(5-chloro-3-{4-[1-(1,1-dimethylethyl)-3-(trifluoromethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}-2- methylphenyl)oxy]-N,N-diethylethanamine 34 2-[(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}phenyl)oxy]-N,N- diethylethanamine 35 4-(4-{5-chloro-2-methyl-3-[(3-pyrrolidin-1-ylpropyl)oxy]phen- yl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 36 4-[4-(5-chloro-2-methyl-3-{[3-(4-methylpiperazin-1- yl)propyl]oxy}phenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine 37 3-bromo-4-(4-{5-chloro-2-methyl-3-[(3-piperidin-1- ylpropyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4- d]pyrimidine 38 3-bromo-4-(4-{5-chloro-2-methyl-3-[(3-morpholin-4- ylpropyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4- d]pyrimidine 39 4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phen- yl}piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidine 40 4-(4-{5-chloro-2-methyl-3-[(3-morpholin-4-ylpropyl)oxy]phen- yl}piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidine 41 4-(4-{5-chloro-2-methyl-3-[(2-morpholin-4- ylethyl)oxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 42 4-(4-{5-chloro-2-methyl-3-[(3-piperidin-1-ylpropyl)oxy]phen- yl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 43 4-[4-(5-chloro-3-{[3-(4-ethylpiperazin-1-yl)propyl]oxy}-2- methylphenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine 44 5-chloro-2-methyl-3-[4-(1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-N-(2-pyrrolidin-1-ylethyl)aniline 45 5-chloro-2-methyl-3-[4-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)piperazin-1-yl]-N-(2-pyrrolidin-1-ylethyl)aniline 46 N′-(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}phenyl)-N,N- dimethylethane-1,2-diamine 47 3-({5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methylphenyl}oxy)-N,N-diethylpropan-1- amine 48 N′-(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}phenyl)-N,N- diethylethane-1,2-diamine 49 5-chloro-2-methyl-N-(2-pyrrolidin-1-ylethyl)-3-{4-[3- (trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1- yl}aniline 50 3-bromo-4-(4-{4-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phen- yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 51 4-(4-{4-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin- 1-yl)-1H-pyrazolo[3,4-d]pyrimidine 52 3-methyl-4-(4-{4-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phen- yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 53 4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phen- yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 54 4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phen- yl}piperazin-1-yl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine 55 4-(4-{5-chloro-2-methyl-3-[(2-piperidin-1- ylethyl)oxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 56 3-[(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}phenyl)oxy]-N,N- diethylpropan-1-amine 57 5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 58 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-fluoro-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 59 4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1- ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 60 3-bromo-4-{4-[5-fluoro-2-methyl-3-(3-pyrrolidin-1- ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 61 4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1- ylpropyl)phenyl]piperazin-1-yl}-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 62 4-(4-{5-chloro-2-methyl-3-[3-(4-methylpiperazin-1- yl)propyl]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine 63 3-bromo-4-(4-pyridin-2-ylpiperazin-1-yl)-1H-pyrazolo[3,4- d]pyrimidine 64 3-bromo-4-[4-(2,4-dimethylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 65 3-bromo-4-{4-[3-(methyloxy)phenyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 66 3-bromo-4-{4-[2-(methyloxy)phenyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 67 3-bromo-4-{4-[4-methyl-3-(3-pyrrolidin-1-ylpropyl)phen- yl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 68 4-(4-{5-chloro-2-methyl-3-[(3-pyrrolidin-1- ylpropyl)oxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 69 4-(4-{5-chloro-2-methyl-3-[(3-piperidin-1- ylpropyl)oxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 70 4-[4-(5-chloro-2-methyl-3-{[3-(4-methylpiperazin-1- yl)propyl]oxy}phenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 71 4-[4-(5-chloro-3-{[3-(4-ethylpiperazin-1-yl)propyl]oxy}-2- methylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 72 3-bromo-4-[4-(5-chloro-2-methyl-3-{[2-(4-methylpiperazin-1- yl)ethyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 73 4-[4-(5-chloro-2-methyl-3-{[2-(4-methylpiperazin-1- yl)ethyl]oxy}phenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 74 3-bromo-4-[4-(5-chloro-3-{[2-(4-ethylpiperazin-1-yl)ethyl]oxy}- 2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 75 3-bromo-4-[4-(3,4-dichlorophenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 76 3-bromo-4-[4-(3,4-difluorophenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 77 3-bromo-4-[4-(2,4-dichlorophenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 78 3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]- 5-fluoro-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 79 5-fluoro-2-methyl-N-(2-pyrrolidin-1-ylethyl)-3-{4-[3- (trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1- yl}aniline 80 4-{4-[3,5-bis(methyloxy)phenyl]piperazin-1-yl}-3-bromo-1H- pyrazolo[3,4-d]pyrimidine 81 4-[4-(5-chloro-3-{[2-(4-ethylpiperazin-1-yl)ethyl]oxy}-2- methylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 82 N-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methylphenyl}-N,N′,N′-trimethylethane- 1,2-diamine 83 3-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-5-chloro-2-methylphenyl}oxy)-N,N-diethylpropan-1- amine 84 3-bromo-4-(4-{5-chloro-2-methyl-3-[(3-pyrrolidin-1- ylpropyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4- d]pyrimidine 85 3-bromo-4-[4-(5-chloro-2-methyl-3-{[3-(4-methylpiperazin-1- yl)propyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 86 3-bromo-4-[4-(5-chloro-3-{[3-(4-ethylpiperazin-1- yl)propyl]oxy}-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 87 3-(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}phenyl)-N,N- diethylpropan-1-amine 88 3-bromo-4-[4-(5-chloro-2-methyl-3-{[(1-methylpiperidin-4- yl)methyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 89 3-bromo-4-[4-(5-chloro-2-methyl-3-{[2-(1-methylpiperidin-4- yl)ethyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 90 4-[4-(5-chloro-2-methyl-3-{[(1-methylpiperidin-4- yl)methyl]oxy}phenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 91 4-[4-(5-chloro-2-methyl-3-{[2-(1-methylpiperidin-4- yl)ethyl]oxy}phenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 92 4-(4-{5-chloro-2-methyl-3-[3-(4-methylpiperazin-1- yl)propyl]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 93 3-bromo-4-[4-(3-chloro-4-fluorophenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 94 1-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]phenyl}ethanone 95 3-bromo-4-[4-(2,5-dichlorophenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 96 3-bromo-4-[4-(3,4-dimethylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 97 3-bromo-4-[4-(4-nitrophenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 98 3-ethyl-4-(4-phenylpiperazin-1-yl)-1H-pyrazolo[3,4- d]pyrimidine 99 3-ethyl-4-{4-[3-(methyloxy)phenyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 100 4-{4-[5-chloro-2-methyl-3-(3-piperidin-1- ylpropyl)phenyl]piperazin-1-yl}-3-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine 101 4-[4-(3,6-dimethylpyrazin-2-yl)piperazin-1-yl]-3-ethyl-1H- pyrazolo[3,4-d]pyrimidine 102 1-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]isoquinoline 103 3-bromo-4-[4-(2,6-dimethylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 104 3-bromo-4-{4-[4-(ethyloxy)phenyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 105 3-bromo-4-[4-(2-ethylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 106 4-{4-[2,4-bis(methyloxy)phenyl]piperazin-1-yl}-3-bromo-1H- pyrazolo[3,4-d]pyrimidine 107 3-bromo-4-(4-pyrazin-2-ylpiperazin-1-yl)-1H-pyrazolo[3,4- d]pyrimidine 108 3-bromo-4-(4-pyrimidin-2-ylpiperazin-1-yl)-1H-pyrazolo[3,4- d]pyrimidine 109 4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-(trifluoromethyl)quinoline 110 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]pyrazine-2-carbonitrile 111 4-[4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl]-3-ethyl-1H- pyrazolo[3,4-d]pyrimidine 112 ethyl 4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-2-(trifluoromethyl)pyrimidine-5-carboxylate 113 4-{4-[3-chloro-5-(methyloxy)phenyl]piperazin-1-yl}-3-ethyl- 1H-pyrazolo[3,4-d]pyrimidine 114 4-[4-(3-bromo-2-chloro-5-fluorophenyl)piperazin-1-yl]-3-ethyl- 1H-pyrazolo[3,4-d]pyrimidine 115 2-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]pyridine-3-carboxamide 116 3-ethyl-4-{4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}- 1H-pyrazolo[3,4-d]pyrimidine 117 3-bromo-4-{4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}- 1H-pyrazolo[3,4-d]pyrimidine 118 3-bromo-4-{4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1- yl}-1H-pyrazolo[3,4-d]pyrimidine 119 2-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]pyrazin-2-yl}oxy)-N,N-dimethylethanamine 120 4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methylquinoline 121 3-bromo-4-[4-(2-nitrophenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 122 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]benzonitrile 123 4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]benzonitrile 124 3-bromo-4-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 125 3-bromo-4-(4-{4-[(phenylmethyl)oxy]phenyl}piperazin-1-yl)- 1H-pyrazolo[3,4-d]pyrimidine 126 4-{4-[5-chloro-2-methyl-3-(methyloxy)phenyl]piperazin-1-yl}- 3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 127 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]pyridine-3-carbonitrile 128 3-bromo-4-[4-(3,5-dichlorophenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 129 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-chloro-5-fluoro-N-(2-pyrrolidin-1-ylethyl)aniline 130 2-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-5-fluoro-N-(2-pyrrolidin-1-ylethyl)aniline 131 3-bromo-4-[4-(2,5-difluorophenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 132 4-[4-(2,5-difluorophenyl)piperazin-1-yl]-3-ethyl-1H- pyrazolo[3,4-d]pyrimidine 133 3-bromo-4-{4-[3-(methyloxy)pyrazin-2-yl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 134 3-bromo-4-[4-(3-chlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 135 3-bromo-4-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}- 1H-pyrazolo[3,4-d]pyrimidine 136 3-bromo-4-{4-[3-chloro-5-(trifluoromethyl)pyridin-2- yl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 137 4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phen- yl}piperazin-1-yl)-3-(1-methylethyl)-1H-pyrazolo[3,4- d]pyrimidine 138 5-chloro-2-methyl-3-{4-[3-(1-methylethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl]piperazin-1-yl}-N-(2-pyrrolidin-1- ylethyl)aniline 139 2-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]phenyl}oxy)-N-ethylacetamide 140 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N,N-diethylpyrimidin-4-amine 141 3-bromo-4-[4-(3-{[(3-methylphenyl)methyl]oxy}phen- yl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 142 3-bromo-4-(4-{3-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin- 1-yl)-1H-pyrazolo[3,4-d]pyrimidine 143 3-bromo-4-[4-(4-furan-2-ylpyrimidin-2-yl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 144 6-{2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]pyrimidin-4-yl}-2H-1,4-benzoxazin-3(4H)-one 145 3-ethyl-4-{4-[2-methyl-3-(methyloxy)phenyl]piperazin-1-yl}- 1H-pyrazolo[3,4-d]pyrimidine 146 N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methylphenyl}-N-methyl-N-(1- methylethyl)ethane-1,2-diamine 147 N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methylphenyl}-N-ethyl-N-methylethane- 1,2-diamine 148 N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-5-chloro-2-methylphenyl}-N,N-dimethylethane-1,2- diamine 149 3-({6-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-2-chloro-5-methylpyrimidin-4-yl}oxy)-N,N-diethylpropan- 1-amine 150 3-bromo-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 151 3-bromo-4-{4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 152 3-bromo-4-(4-phenylpiperazin-1-yl)-1H-pyrazolo[3,4- d]pyrimidine 153 3-bromo-4-[4-(4-fluorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 154 3-bromo-4-[4-(4-chlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 155 3-bromo-4-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 156 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidin-6-amine 157 3-bromo-4-[4-(4-bromophenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 158 3-bromo-4-[3-methyl-4-(3-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 159 4-[4-(3-bromo-5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-6-amine 160 4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phen- yl}piperazin-1-yl)-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine 161 5-chloro-3-[4-(3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 162 5-chloro-2-methyl-3-{4-[3-(2-methylpropyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl]piperazin-1-yl}-N-(2-pyrrolidin-1- ylethyl)aniline 163 4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1- ylethyl)oxy]phenyl}piperazin-1-yl)-3-(2-methylpropyl)-1H- pyrazolo[3,4-d]pyrimidine 164 3-bromo-4-[(3S)-4-(5-chloro-2-methylphenyl)-3- methylpiperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 165 5-bromo-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methylaniline 166 2-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]phenyl}oxy)-N-cyclopropylacetamide 167 3-bromo-4-(4-{3-[(2-piperidin-1-ylethyl)oxy]pyrazin-2- yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 168 4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]- 6,7-bis(methyloxy)quinazoline 169 2-({3-chloro-5-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]phenyl}oxy)-N,N-diethylethanamine 170 4-{4-[2-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl}-3- ethyl-1H-pyrazolo[3,4-d]pyrimidine 171 3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]- 2-methyl-5-[(2-methylpropyl)oxy]-N-(2-pyrrolidin-1- ylethyl)aniline 172 3-({4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-6-chloro-5-methylpyrimidin-2-yl}oxy)-N,N-diethylpropan- 1-amine 173 3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]- 2-methyl-5-[(phenylmethyl)oxy]-N-(2-pyrrolidin-1- ylethyl)aniline 174 3-bromo-4-[(3R)-4-(5-chloro-2-methylphenyl)-3- methylpiperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 175 3-[(2S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2- methylpiperazin-1-yl]-4-methyl-N-phenylbenzamide 176 3-[(2S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2- methylpiperazin-1-yl]-4-methyl-N-(phenylmethyl)benzamide 177 methyl 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-4-methylbenzoate 178 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methylbenzoic acid 179 (2E)-3-(4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1- ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)prop-2-enoic acid 180 3-(4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1- ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)prop-2-yn-1-ol 181 4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-(5-chloro-2- methylphenyl)piperazin-2-one 182 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-[(2-methylpropyl)oxy]-N-(2-pyrrolidin-1- ylethyl)aniline 183 N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-2-methyl-5-[(2-methylpropyl)oxy]phenyl}-N,N- diethylethane-1,2-diamine 184 methyl 3-bromo-5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-4-methylbenzoate 185 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-N-phenylbenzamide 186 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N,4-dimethylbenzamide 187 2-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]phenyl}oxy)-N,N-diethylethanamine 188 methyl 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1- ylethyl)amino]benzoate 189 3-bromo-5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-4-methyl-N-phenylbenzamide 190 3-bromo-5-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-4-methyl-N-phenylbenzamide 191 N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-5-chloro-2-methylphenyl}-N-methyl-N-(1- methylethyl)ethane-1,2-diamine 192 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-N-phenyl-5-[(2-pyrrolidin-1- ylethyl)amino]benzamide 193 N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-2-methyl-5-[(2-methylpropyl)oxy]phenyl}-N,N- dimethylethane-1,2-diamine 194 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N,N,4-trimethylbenzamide 195 3-[4-(3-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-N-(2-methylpropyl)benzamide 196 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N,N,4-trimethyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 197 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2- oxopiperazin-1-yl]-4-methyl-N-phenylbenzamide 198 3-[(2R)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2- (hydroxymethyl)piperazin-1-yl]-4-methyl-N-phenylbenzamide 199 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-(pyrrolidin-1-ylcarbonyl)-N-(2-pyrrolidin-1- ylethyl)aniline 200 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N,4-dimethyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 201 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N-(4-chlorophenyl)-4-methyl-5-[(2-pyrrolidin-1- ylethyl)amino]benzamide 202 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N-(2-chlorophenyl)-4-methyl-5-[(2-pyrrolidin-1- ylethyl)amino]benzamide 203 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-[(cyclopropylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 204 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-[(3-methylbutyl)oxy]-N-(2-pyrrolidin-1- ylethyl)aniline 205 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-[(2-ethylbutyl)oxy]-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 206 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-(butyloxy)-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 207 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-N-(1-methylethyl)-5-[(2-pyrrolidin-1- ylethyl)amino]benzamide 208 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N,4-dimethyl-N-(1-methylethyl)-5-[(2-pyrrolidin-1- ylethyl)amino]benzamide 209 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-[(cyclobutylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 210 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-(ethyloxy)-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 211 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N-[2-(dimethylamino)ethyl]-4-methylbenzamide 212 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N-(1,1-dimethylethyl)-4-methyl-5-[(2-pyrrolidin-1- ylethyl)amino]benzamide 213 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-N-pyridin-3-yl-5-[(2-pyrrolidin-1- ylethyl)amino]benzamide 214 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-[(2-fluoro-2-methylpropyl)oxy]-2-methyl-N-(2-pyrrolidin- 1-ylethyl)aniline 215 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-[(cyclohexylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 216 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-[(cyclopentylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 217 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N-ethyl-4-methyl-5-[(2-pyrrolidin-1- ylethyl)amino]benzamide 218 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-[(1-methylethyl)oxy]-N-(2-pyrrolidin-1- ylethyl)aniline 219 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-[(2,2-dimethylpropyl)oxy]-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 220 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-[(tetrahydrofuran-2- ylmethyl)oxy]aniline 221 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-{[2-(methyloxy)ethyl]oxy}-N-(2-pyrrolidin-1- ylethyl)aniline 222 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-(propyloxy)-N-(2-pyrrolidin-1-ylethyl)aniline 223 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-{[2-(dimethylamino)ethyl]amino}-4-methyl-N- phenylbenzamide 224 N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-5-[(2-fluoro-2-methylpropyl)oxy]-2-methylphenyl}-N,N- dimethylethane-1,2-diamine 225 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-{[2-(dimethylamino)ethyl]amino}-4-methyl-N-(1- methylethyl)benzamide 226 1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}pentan- 1-one 227 N′-(3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2- methylphenyl)-N,N-dimethylethane-1,2-diamine 228 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methyl-N- (2-pyrrolidin-1-ylethyl)aniline 229 5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-N-(2-pyrrolidin-1-ylethyl)biphenyl-3-amine 230 1-(3-{5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-4-methylbiphenyl-3-yl}propyl)pyridinium 231 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-(1,3-thiazol-2- yl)aniline 232 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzoic acid 233 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-(phenylethynyl)-N-(2-pyrrolidin-1-ylethyl)aniline 234 {3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-5-[(2-pyrrolidin-1- ylethyl)amino]phenyl}(phenyl)methanone 235 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-ethynyl-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 236 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-(3,3-dimethylbut-1-yn-1-yl)-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 237 3-bromo-4-{4-[5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2- methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 238 3-bromo-4-{4-[2-methyl-5-[(2-methylpropyl)oxy]-3-(3- pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4- d]pyrimidine 239 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-N-(2-pyrrolidin- 1-ylethyl)aniline 240 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(2-pyrrolidin- 1-ylethyl)aniline 241 1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}propan- 1-one 242 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-(3,3-dimethylbutyl)-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 243 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-ethyl-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 244 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-[2- (trimethylsilyl)ethyl]aniline 245 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-(2-phenylethyl)-N-(2-pyrrolidin-1-ylethyl)aniline 246 1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}butan- 1-one 247 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N,4-dimethyl-N-(methyloxy)-5-[(2-pyrrolidin-1- ylethyl)amino]benzamide 248 3-bromo-4-[4-(3-bromo-5-{[2,3-difluoro-2- (fluoromethyl)propyl]oxy}-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 249 4-[4-(3-bromo-5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2- methylphenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine 250 1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-4-methyl-5-[(2-pyrrolidin-1- ylethyl)amino]phenyl}ethanone 251 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-[(difluoromethyl)oxy]-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 252 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-{[(difluoromethyl)oxy]methyl}-2-methyl-N-(2-pyrrolidin- 1-ylethyl)aniline 253 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-(methyloxy)-N-(2-pyrrolidin-1-ylethyl)aniline 254 5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-3-[4-(3-ethyl-1H- pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2- pyrrolidin-1-ylethyl)aniline 255 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-3,5,6-trifluoro-N-(3-methylbutyl)pyridin-4-amine 256 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-N-[(cyclopropylmethyl)oxy]-4-methyl-5-[(2-pyrrolidin-1- ylethyl)amino]benzamide 257 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(2-pyrrolidin- 1-ylethyl)aniline 258 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-(ethylsulfonyl)-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 259 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-5-(methylsulfonyl)-N-(2-pyrrolidin-1- ylethyl)aniline 260 1-{3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}pentan-1- one 261 3-bromo-4-[4-(5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2- methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 262 6-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-3,5-difluoro-N~4~-(3-methylbutyl)-N~2~-(2-pyrrolidin-1- ylethyl)pyridine-2,4-diamine 263 3-bromo-5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-N-(2-pyrrolidin-1-ylethyl)aniline 264 3-bromo-4-[4-(3′,4′,6-trifluoro-4-methylbiphenyl-3-yl)piperazin- 1-yl]-1H-pyrazolo[3,4-d]pyrimidine 265 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-chloro-N-(2-pyrrolidin-1-ylethyl)aniline 266 {3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}methanol 267 3-bromo-4-(4-{4-methyl-2′-[(2-pyrrolidin-1-ylethyl)oxy]biphen- yl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 268 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-{[(2,2-difluorocyclopropyl)methyl]oxy}-2-methyl-N-(2- pyrrolidin-1-ylethyl)aniline 269 5-bromo-3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 270 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-[(ethyloxy)methyl]-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 271 3-[4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-1-methyl-6-(trifluoromethyl)-1H-benzimidazol-2- yl]propan-1-ol 272 1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}-4,4,4- trifluorobutan-1-one 273 {3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-4-methyl-5-[(2-pyrrolidin-1- ylethyl)amino]phenyl}(cyclopropyl)methanone 274 3-({3′-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-4′-methylbiphenyl-2-yl}oxy)-N,N-dimethylpropan-1-amine 275 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-5-(1,1-difluorobutyl)-2-methyl-N-(2-pyrrolidin-1- ylethyl)aniline 276 3-bromo-4-(4-{4-methyl-2′-[(3-morpholin-4-ylpropyl)oxy]bi- phenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 277 3-bromo-4-(4-{4-methyl-2′-[(2-morpholin-4-ylethyl)oxy]bi- pphenyl-3-yl}piperazin-1-yl)-1H-yrazolo[3,4-d]pyrimidine 278 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-{[(2,2,2- trifluoroethyl)oxy]methyl}aniline 279 1-[2-({3′-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-4′-methylbiphenyl-2-yl}oxy)ethyl]pyrrolidine- 2,5-dione 280 3-bromo-4-(4-{3′-fluoro-4-methyl-2′-[(2-pyrrolidin-1- ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4- d]pyrimidine 281 1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}butan-1-one 282 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-[(3,3,3- trifluoropropyl)oxy]aniline 283 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-[(2,2,2- trifluoroethyl)oxy]aniline 284 1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin- 1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}butan- 1-ol 285 3-bromo-4-(4-{4-chloro-2′-[(2-pyrrolidin-1-ylethyl)oxy]bi- phenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 286 3-[4-(4-{5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2- methyl-3-[(2-pyrrolidin-1-ylethyl)amino]phenyl}piperazin-1-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl]prop-2-yn-1-ol 287 3-bromo-4-(4-{4-chloro-4′-fluoro-2′-[(2-pyrrolidin-1- ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4- d]pyrimidine 288 3-bromo-4-(4-{4-methyl-3′-[(2-pyrrolidin-1-ylethyl)oxy]bi- phenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 289 (2E)-3-[4-(4-{5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2- methyl-3-[(2-pyrrolidin-1-ylethyl)amino]phenyl}piperazin-1-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl]prop-2-enoic acid 290 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-[4,4,4-trifluoro-1,1- bis(methyloxy)butyl]aniline 291 6-(4-phenylpiperazin-1-yl)-9H-purine 292 6-[4-(3-chlorophenyl)piperazin-1-yl]-9H-purine 293 4-(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine 294 4-[4-(3-chlorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3- d]pyrimidine 295 4-(4-phenylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 296 4-[4-(3-chlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 297 6-[4-(2-chlorophenyl)piperazin-1-yl]-9H-purine 298 6-[4-(2-fluorophenyl)piperazin-1-yl]-9H-purine 299 4-[4-(2-methylphenyl)piperazin-1-yl]-7H-pyrrolo[2,3- d]pyrimidine 300 4-{4-[2-(methyloxy)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3- d]pyrimidine 301 4-{4-[3-(methyloxy)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3- d]pyrimidine 302 4-{4-[4-(methyloxy)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3- d]pyrimidine 303 4-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3- d]pyrimidine 304 6-{4-[4-(methyloxy)phenyl]piperazin-1-yl}-9H-purine 305 6-{4-[2-(methyloxy)phenyl]piperazin-1-yl}-9H-purine 306 6-[4-(4-chlorophenyl)piperazin-1-yl]-9H-purine 307 6-[4-(4-fluorophenyl)piperazin-1-yl]-9H-purine 308 4-[4-(4-chlorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3- d]pyrimidine 309 4-[4-(2-chlorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3- d]pyrimidine 310 4-[4-(4-fluorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3- d]pyrimidine 311 4-[4-(2-fluorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3- d]pyrimidine 312 6-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-9H-purine 313 6-[4-(2-methylphenyl)piperazin-1-yl]-9H-purine 314 4-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 315 4-[4-(2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 316 4-[4-(3-chlorophenyl)piperazin-1-yl]-3-methyl-1H-pyrazolo[3,4- d]pyrimidine 317 3-methyl-4-[4-(2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 318 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 319 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-methyl-1H- pyrazolo[3,4-d]pyrimidine 320 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-methyl-6- phenyl-1H-pyrazolo[3,4-d]pyrimidine 321 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-ethyl-1H- pyrazolo[3,4-d]pyrimidine 322 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-6-methyl-1H- pyrazolo[3,4-d]pyrimidine 323 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-6-ethyl-1H- pyrazolo[3,4-d]pyrimidine 324 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-6-(1- methylethyl)-1H-pyrazolo[3,4-d]pyrimidine 325 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-phenyl-1H- pyrazolo[3,4-d]pyrimidine 326 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-({[2- (methyloxy)ethyl]oxy}methyl)-1H-pyrazolo[3,4-d]pyrimidine 327 3-bromo-4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 328 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-propyl-1H- pyrazolo[3,4-d]pyrimidine 329 4-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}phenol 330 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-N-phenyl-1H- pyrazolo[3,4-d]pyrimidin-3-amine 331 4-[4-(3-chlorophenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine 332 4-{4-[5-chloro-2-(methyloxy)phenyl]piperazin-1-yl}-3-ethyl- 1H-pyrazolo[3,4-d]pyrimidine 333 3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}phenol 334 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-{3- [(phenylmethyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidine 335 3-(1,3-benzodioxol-5-yl)-4-[4-(5-chloro-2-methyl- phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 336 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(2-thienyl)-1H- pyrazolo[3,4-d]pyrimidine 337 3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}aniline 338 3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}benzoic acid 339 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(4- methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine 340 N-(4-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)acetamide 341 4-[4-(3-chlorophenyl)-1,4-diazepan-1-yl]-3-ethyl-1H- pyrazolo[3,4-d]pyrimidine 342 4-[5-(3-chlorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-ethyl- 1H-pyrazolo[3,4-d]pyrimidine 343 4-(4-{3-chloro-4-[(2-morpholin-4-ylethyl)oxy]phenyl}piperazin- 1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 344 methyl 1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)piperazine-2-carboxylate 345 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-methylbut- 2-en-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 346 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3- (trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 347 methyl 4-(3-chlorophenyl)-1-(3-ethyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)piperazine-2-carboxylate 348 4-(4-{3-chloro-4-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin- 1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 349 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(1- methylethyl)-1H-pyrazolo[3,4-d]pyrimidine 350 1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazine-2-carboxylic acid 351 1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-N-methylpiperazine-2-carboxamide 352 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3- (phenylmethyl)-1H-pyrazolo[3,4-d]pyrimidine 353 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(2- methylpropyl)-1H-pyrazolo[3,4-d]pyrimidine 354 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[4- (methyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidine 355 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(4- fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine 356 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[4- (phenyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidine 357 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-{4-[(piperidin- 4-ylmethyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidine 358 1-(3-chlorophenyl)-N-[2-(dimethylamino)ethyl]-4-(3-ethyl-1H- pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-2-carboxamide 359 4-[4-(5-chloro-2-methyl-3-morpholin-4-ylphenyl)piperazin-1- yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 360 4-(3-chlorophenyl)-1-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-N-methylpiperazine-2-carboxamide 361 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[2- (methyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidine 362 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-pyridin-4-yl- 1H-pyrazolo[3,4-d]pyrimidine 363 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[3- (methyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidine 364 4-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}benzonitrile 365 [5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-(methyloxy)phenyl]methanol 366 methyl 5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-(methyloxy)benzoate 367 (2E)-3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}prop-2-enoic acid 368 3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}propanoic acid 369 3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}propan-1-ol 370 methyl (2E)-3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]- 1H-pyrazolo[3,4-d]pyrimidin-3-yl}prop-2-enoate 371 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-{4-[(2- morpholin-4-ylethyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidine 372 5-chloro-N-[2-(dimethylamino)ethyl]-3-[4-(3-ethyl-1H- pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2- (methyloxy)benzamide 373 4-(4-{5-chloro-2-(methyloxy)-3-[(4-methylpiperazin-1- yl)carbonyl]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine 374 2-(dimethylamino)ethyl 5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)piperazin-1-yl]-2-(methyloxy)benzoate 375 1-[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-(methyloxy)phenyl]-N,N- dimethylmethanamine 376 N′-{[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-(methyloxy)phenyl]methyl}-N,N- dimethylethane-1,2-diamine 377 [1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-2-yl]methanol 378 3-[(4-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)oxy]-N,N- dimethylpropan-1-amine 379 2-chloro-4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-5-methylphenol 380 1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-N-(1-methylpiperidin-4-yl)piperazine-2-carboxamide 381 1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-N-(2-morpholin-4-ylethyl)piperazine-2-carboxamide 382 2-{[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-(methyloxy)phenyl]oxy}-N,N- dimethylethanamine 383 3-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methylphenyl}-N,N-dimethylprop-2-yn-1- amine 384 N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methylphenyl}-N,N-dimethylethane-1,2- diamine 385 1,1-dimethylethyl (2E)-3-{4-[4-(5-chloro-2- methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3- yl}prop-2-enoate 386 3-({2-chloro-4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-5-methylphenyl}oxy)-N,N-dimethylpropan-1- amine 387 2-({2-chloro-4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-5-methylphenyl}oxy)-N,N- dimethylethanamine 388 4-{4-[5-chloro-2-methyl-4-(methyloxy)phenyl]piperazin-1-yl}- 3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 389 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(4- methylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 390 3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}-N,N-diethylprop-2-yn-1-amine 391 3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}prop-2-yn-1-ol 392 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(piperidin-4- ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine 393 phenylmethyl (3aR,6aS)-5-({4-[4-(5-chloro-2- methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3- yl}methylidene)hexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate 394 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[(E)- (3aR,6aS)-hexahydrocyclopenta[c]pyrrol-5(1H)-ylidenemethyl]- 1H-pyrazolo[3,4-d]pyrimidine 395 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-pyrrolidin- 1-ylprop-1-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 396 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[3-(4- methylpiperazin-1-yl)prop-1-yn-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 397 3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}-N,N-diethylpropan-1-amine 398 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-pyrrolidin- 1-ylpropyl)-1H-pyrazolo[3,4-d]pyrimidine 399 4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(1,2,3,6- tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine 400 3-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]-2-methylphenyl}-N,N-diethylpropan-1-amine 401 4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1- ylpropyl)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4- d]pyrimidine and a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, solvate, or hydrate thereof.

TABLE 2b Additional Representative AKT Inhibitors Entry Name 1 [1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4- chlorophenyl)methanol 2 2-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylethanamine 3 3-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylpropan-1-amine 4 3-bromo-4-{4-[(4-bromophenyl)methyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 5 {4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4- chlorophenyl)methyl]piperazin-2-yl}methanol 6 N′-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-chlorophenyl)methyl]-N,N-diethylethane-1,2-diamine 7 3-bromo-4-(4-{[4-(1,1-dimethylethyl)phenyl]methyl}piperazin-1- yl)-1H-pyrazolo[3,4-d]pyrimidine 8 4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4- chlorophenyl)methyl]piperazin-2-one 9 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2- (4-chlorophenyl)-N-[2-(dimethylamino)ethyl]acetamide 10 N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]- N-(4-chlorophenyl)-N′,N′-diethylpropane-1,3-diamine 11 3-bromo-4-(4-{[4-(trifluoromethyl)phenyl]methyl}piperazin-1-yl)- 1H-pyrazolo[3,4-d]pyrimidine 12 N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]- N-(4-chlorophenyl)-N′-[2-(dimethylamino)ethyl]urea 13 N-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-chlorophenyl)methyl]-N′-[2-(dimethylamino)ethyl]urea 14 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxopiperazin- 1-yl]-2-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]acetamide 15 2-(dimethylamino)ethyl [1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)piperidin-4-yl](4-chlorophenyl)carbamate 16 3-bromo-4-{4-[(4-chloro-3-fluorophenyl)methyl]piperazin-1-yl}- 1H-pyrazolo[3,4-d]pyrimidine 17 3-bromo-4-{4-[(4-chloro-2-fluorophenyl)methyl]piperazin-1-yl}- 1H-pyrazolo[3,4-d]pyrimidine 18 N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]- N-(4-chlorophenyl)-N′,N′-diethylethane-1,2-diamine 19 3-bromo-4-{4-[(4-chlorophenyl)methyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 20 [1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4- fluorophenyl)methanone 21 N-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-chlorophenyl)methyl]-N′,N′-diethyl-N-methylethane-1,2- diamine 22 [1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4- fluorophenyl)methanol 23 3-bromo-4-(4-{[2-fluoro-4-(trifluoromethyl)phen- yl]methyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 24 N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]- N-(4-chlorophenyl)-N~3~,N~3~-diethyl-beta-alaninamide 25 2-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-fluorophenyl)methyl]oxy}-N,N-dimethylethanamine 26 N-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-chlorophenyl)methyl]-N~3~,N~3~-diethyl-beta-alaninamide 27 3-bromo-4-{4-[(3,4-dichlorophenyl)methyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 28 N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]- N-(4-chlorophenyl)-N′-[2-(dimethylamino)ethyl]ethanediamide 29 N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]- N-(4-chlorophenyl)-2-(diethylamino)ethanesulfonamide 30 4-[4-(biphenyl-4-ylmethyl)piperazin-1-yl]-3-bromo-1H- pyrazolo[3,4-d]pyrimidine 31 3-bromo-4-{(3S)-4-[(4-chlorophenyl)methyl]-3-methylpiperazin-1- yl}-1H-pyrazolo[3,4-d]pyrimidine 32 3-bromo-4-(4-{[4-(methyloxy)phenyl]methyl}piperazin-1-yl)-1H- pyrazolo[3,4-d]pyrimidine 33 4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-[3- (trifluoromethyl)phenyl]piperazine-1-carboxamide 34 3-bromo-4-{4-[(4-fluorophenyl)methyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 35 N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]- N-(4-chlorophenyl)pent-4-enamide 36 3-bromo-4-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperazin- 1-yl]-1H-pyrazolo[3,4-d]pyrimidine 37 4-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-bromo-1H- pyrazolo[3,4-d]pyrimidine 38 [1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4- chlorophenyl)methanone 39 3-bromo-4-(4-{[4-(phenyloxy)phenyl]methyl}piperazin-1-yl)-1H- pyrazolo[3,4-d]pyrimidine 40 3-bromo-4-{4-[(3,4-dichlorophenyl)methyl]piperidin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 41 4-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]methyl}-N,N-dimethylaniline 42 methyl 4-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazin-1-yl]methyl}benzoate 43 3-bromo-4-{4-[(2E)-3-phenylprop-2-enoyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 44 1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-[(4-chlorophen- yl)methyl]-N-[3-(diethylamino)propyl]piperidine-4-carboxamide 45 3-bromo-4-{4-[(2-bromophenyl)methyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 46 3-bromo-4-{4-[(2-chlorophenyl)methyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 47 3-bromo-4-{4-[(2,4-dichlorophenyl)methyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 48 3-bromo-4-{4-[(2-chloro-4-fluorophenyl)methyl]piperazin-1-yl}- 1H-pyrazolo[3,4-d]pyrimidine 49 1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-(4-chlorophenyl)- N-[3-(diethylamino)propyl]piperidine-4-carboxamide 50 3-bromo-4-[4-(phenylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 51 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]- N-pyridin-2-ylacetamide 52 3-bromo-4-[4-(1H-imidazol-2-ylmethyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 53 3-bromo-4-(4-{[3-(phenyloxy)phenyl]methyl}piperazin-1-yl)-1H- pyrazolo[3,4-d]pyrimidine 54 3-bromo-4-{4-[(3-methylphenyl)methyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 55 3-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]methyl}benzonitrile 56 3-bromo-4-{4-[(2-chloro-6-fluorophenyl)methyl]piperazin-1-yl}- 1H-pyrazolo[3,4-d]pyrimidine 57 3-bromo-4-[4-(1-phenylethyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 58 3-bromo-4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 59 1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(4- chlorophenyl)piperidin-4-amine 60 3-bromo-4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 61 3-bromo-4-(4-{[2,3,4-tris(methyloxy)phenyl]methyl}piperazin-1- yl)-1H-pyrazolo[3,4-d]pyrimidine 62 3-bromo-4-[4-({3-[(phenylmethyl)oxy]phenyl}methyl)piperazin-1- yl]-1H-pyrazolo[3,4-d]pyrimidine 63 3-bromo-4-[4-(naphthalen-1-ylmethyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 64 3-bromo-4-(4-{[5-(4-chlorophenyl)furan-2-yl]methyl}piperazin-1- yl)-1H-pyrazolo[3,4-d]pyrimidine 65 3-bromo-4-[4-({4-[(4-fluorophenyl)oxy]-3-nitro- phenyl}methyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 66 3-bromo-4-[4-(furan-2-ylcarbonyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 67 3-bromo-4-[4-(1H-indol-6-ylcarbonyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 68 3-bromo-4-{4-[2-(2-thienyl)ethyl]piperazin-1-yl}-1H-pyrazolo[3,4- d]pyrimidine 69 3-bromo-4-[4-(3-pyrrolidin-1-ylpropyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 70 3-bromo-4-[4-(cyclohexylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 71 3-bromo-4-{4-[(10-chloroanthracen-9-yl)methyl]piperazin-1-yl}- 1H-pyrazolo[3,4-d]pyrimidine 72 3-bromo-4-[4-(1-methylpropyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine 73 4-(4-{[4,6-bis(methyloxy)pyrimidin-2-yl]methyl}piperazin-1-yl)-3- bromo-1H-pyrazolo[3,4-d]pyrimidine 74 3-bromo-4-{4-[2-(methyloxy)ethyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 75 3-bromo-4-[4-(2-morpholin-4-yl-2-oxoethyl)piperazin-1-yl]-1H- pyrazolo[3,4-d]pyrimidine 76 3-bromo-4-{4-[3-(methyloxy)propyl]piperazin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 77 4-{4-[[4,6-bis(methyloxy)pyrimidin-2-yl](phenyl)methyl]piperazin- 1-yl}-3-bromo-1H-pyrazolo[3,4-d]pyrimidine 78 3-bromo-4-[4-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5- yl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 79 3-bromo-4-[4-({4-[(phenylmethyl)oxy]phenyl}methyl)piperazin-1- yl]-1H-pyrazolo[3,4-d]pyrimidine 80 3-bromo-4-[4-({3-chloro-4-[(phenylmethyl)oxy]phen- yl}methyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 81 4-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]methyl}-N-(3-morpholin-4-ylpropyl)benzamide 82 4-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1- yl]methyl}-N-[3-(methyloxy)propyl]benzamide 83 2-[({4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4- chlorophenyl)methyl]piperazin-2-yl}methyl)oxy]-N,N- dimethylethanamine 84 3-bromo-4-[4-({4-[(4-chlorophenyl)oxy]-3- nitrophenyl}methyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 85 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]- N,N-dimethylacetamide 86 2-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylethanamine 87 N-(4-bromo-3-fluorophenyl)-N-[1-(3-bromo-1H-pyrazolo[3,4- d]pyrimidin-4-yl)piperidin-4-yl]-N′-[2-(dimethylamino)ethyl]urea 88 2-({(R)-(4-chlorophenyl)[1-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)piperidin-4-yl]methyl}oxy)-N,N-dimethylethanamine 89 2-{[(S)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylethanamine 90 3-bromo-4-(4-{(R)-(4-chlorophenyl)[(2-pyrrolidin-1- ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 91 1-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-1- (4-chlorophenyl)-4-(dimethylamino)butan-1-ol 92 2-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-chloro-3-fluorophenyl)methyl]oxy}-N,N-dimethylethanamine 93 3-bromo-4-(4-{(R)-(4-chlorophenyl)[(2-piperidin-1- ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 94 4-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-4- (4-chlorophenyl)-N,N-dimethylbutan-1-amine 95 3-bromo-4-(4-{(R)-(4-chlorophenyl)[(2-morpholin-4- ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 96 1-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-1- (4-fluorophenyl)-N-(furan-2-ylmethyl)-N-methylmethanamine 97 1-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-1- m(4-fluorophenyl)-N-ethyl-N-(pyridin-2-ylmethyl)methanamine 98 4-{[{[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-fluorophenyl)methyl}(methyl)amino]methyl}-N,N- dimethylaniline 99 [4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl](1H- indol-6-yl)methanol 100 3-bromo-4-(4-{(R)-(4-chloro-3-fluorophenyl)[(2-pyrrolidin-1- ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 101 3-bromo-4-{4-[(4-chlorophenyl)oxy]piperidin-1-yl}-1H- pyrazolo[3,4-d]pyrimidine 102 2-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl](4-chlorophenyl)methyl]oxy}-N,N-diethylethanamine 103 2-{[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4- yl]oxy}-5-chloro-N-(2-pyrrolidin-1-ylethyl)aniline and a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, solvate, or hydrate thereof.

TABLE 3a Representative c-MET Inhibitors Cmpd No. Name 1 N-(4-fluorophenyl)-N′-[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4- yloxy)phenyl]propanediamide 2 N-(4-fluorophenyl)-N′-[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4- yloxy)phenyl]cyclopropane-1,1-dicarboxamide 3 N-({[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4- yloxy)phenyl]amino}carbonothioyl)-2-phenylacetamide 4 N-(4-fluorophenyl)-N′-(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)cyclopropane-1,1- dicarboxamide 5 2-phenyl-N-{[(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl]oxy}phenyl)amino]carbonothioyl}acetamide 6 N-(4-fluorophenyl)-N′-[4-(1H-pyrazolo[3,4-d]pyrimidin-4- yloxy)phenyl]cyclopropane-1,1-dicarboxamide 7 2-phenyl-N-({[4-(1H-pyrazolo[3,4-d]pyrimidin-4- yloxy)phenyl]amino}carbonothioyl)acetamide 8 N-(4-fluorophenyl)-N′-(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H- purin-6-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide 9 2-phenyl-N-{[(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- yl]oxy}phenyl)amino]carbonothioyl}acetamide 10 N-(4-fluorophenyl)-N′-[4-(9H-purin-6-yloxy)phenyl]cyclopropane- 1,1-dicarboxamide 11 2-phenyl-N-({[4-(9H-purin-6- yloxy)phenyl]amino}carbonothioyl)acetamide 12 N-{3-fluoro-4-[(6-{[(2-morpholin-4-ylethyl)amino]carbonyl}-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide and a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, solvate, or hydrate thereof.

TABLE 3b Additional Representative c-MET Inhibitors Entry Name 1 N-[({3-fluoro-4-[(6-(methyloxy)-7-{[(3aR,6aS)- octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4- yl)oxy]phenyl}amino)carbonothioyl]-2-phenylacetamide 2 N-{[(3-fluoro-4-{[7-({[(3aR,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- yl]oxy}phenyl)amino]carbonothioyl}-2-phenylacetamide 3 N-{[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)(methyl)amino]carbonothioyl}-2-phenylacetamide 4 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)imidazolidin-2-one 5 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3- (phenylmethyl)imidazolidin-2-one 6 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3- (phenylacetyl)imidazolidin-2-one 7 ethyl [(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)amino](oxo)acetate 8 N-{[(4-{[6,7-bis(methyloxy)quinazolin-4-yl]amino}-3- fluorophenyl)amino]carbonothioyl}-2-phenylacetamide 9 N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N- methyl-N-(2-phenylethyl)sulfamide 10 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3- (phenylmethyl)-1,2,4-oxadiazol-5-amine 11 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)piperidin-2-one 12 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- (phenylmethyl)ethanediamide 13 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-4- phenyl-1,3-thiazol-2-amine 14 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- (2-phenylethyl)ethanediamide 15 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-1- phenylmethanesulfonamide 16 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-2- phenylethanesulfonamide 17 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N- (phenylmethyl)benzenesulfonamide 18 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-methyl-N- (phenylmethyl)benzenesulfonamide 19 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-(2- phenylethyl)benzenesulfonamide 20 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-methyl-N- (2-phenylethyl)benzenesulfonamide 21 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-(3- phenylpropyl)benzenesulfonamide 22 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)pyrrolidin-2-one 23 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl (phenylmethyl)carbamate 24 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl (2- phenylethyl)carbamate 25 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-methyl-N- (3-phenylpropyl)benzenesulfonamide 26 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- phenylethanediamide 27 N-{[(3-fluoro-4-{[7-{[(2-methyloctahydrocyclopenta[c]pyrrol-5- yl)methyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}phenyl)amino]carbonothioyl}-2-phenylacetamide 28 N-[(Z)-[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)amino](imino)methyl]-2-phenylacetamide 29 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-[2- (phenyloxy)ethyl]benzenesulfonamide 30 N,N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- bis-(3-phenylpropane-1-sulfonamide) 31 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3- phenylpropane-1-sulfonamide 32 N2-[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)sulfonyl]-N1-phenylglycinamide 33 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-2- phenylacetamide 34 N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3- yl)amino]carbonothioyl}-2-phenylacetamide 35 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,3-benzothiazol-2- amine 36 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3- benzothiazol-2-amine 37 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-phenylacetamide 38 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- (2-morpholin-4-ylethyl)ethanediamide 39 benzyl-{[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro- phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester 40 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N2-(phenylmethyl)glycinamide 41 N2-acetyl-N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N2-(phenylmethyl)glycinamide 42 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,3-benzothiazol-2- yl)-2-phenylacetamide 43 benzyl-{[6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3- ylcarbamoyl]-methyl}-carbamic acid tert-butyl ester 44 N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2- (phenylmethyl)glycinamide 45 N2-acetyl-N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3- yl)-N2-(phenylmethyl)glycinamide 46 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-3- phenylpropanamide 47 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-4- phenylbutanamide 48 N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2- methyl-N2-(phenylmethyl)glycinamide 49 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- {2-[4-(methyloxy)phenyl]ethyl}ethanediamide 50 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N2-methyl-N2-(phenylmethyl)glycinamide 51 4-[(2-amino-1,3-benzothiazol-6-yl)oxy]-6,7-bis(methyloxy)-1-(2- oxo-2-phenylethyl)quinolinium 52 N-{[(4-{[6,7-bis(methyloxy)quinolin-4- yl]amino}phenyl)amino]carbonothioyl}-2-phenylacetamide 53 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-3-phenylpropanamide 54 N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)amino]carbonothioyl}-2-phenylacetamide 55 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- (2,3-dihydro-1H-inden-1-yl)ethanediamide 56 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- (2,3-dihydro-1H-inden-2-yl)ethanediamide 57 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- (1,2,3,4-tetrahydronaphthalen-1-yl)ethanediamide 58 N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N- (2-phenylethyl)-N-(phenylmethyl)sulfamide 59 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N2-(trifluoroacetyl)glycinamide 60 N-{[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro- phenylcarbamoyl]-methyl}-benzamide 61 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N′-(4- fluorophenyl)propanediamide 62 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- [(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]ethanediamide 63 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- [2-(4-methylphenyl)ethyl]ethanediamide 64 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- (2-phenylpropyl)ethanediamide 65 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- [2-(4-chlorophenyl)ethyl]ethanediamide 66 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N,N′-bis(phenylmethyl)sulfamide 67 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N,N′-bis(2-phenylethyl)sulfamide 68 ethyl [(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin- 3-yl)amino](oxo)acetate 69 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-(2-phenylethyl)ethanediamide 70 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-(4-fluorophenyl)propanediamide 71 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- (1,2,3,4-tetrahydronaphthalen-2-yl)ethanediamide 72 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- [2-(1-methylpyrrolidin-2-yl)ethyl]ethanediamide 73 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- [2-(phenyloxy)ethyl]ethanediamide 74 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- [2-hydroxy-1-(phenylmethyl)ethyl]urea 75 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3- [(4-methylphenyl)sulfonyl]-4-(phenylmethyl)imidazolidin-2-one 76 N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N- methyl-N-(2-phenylethyl)ethanediamide 77 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- {[3-(trifluoromethyl)phenyl]methyl}ethanediamide 78 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- {2-[3-(trifluoromethyl)phenyl]ethyl}ethanediamide 79 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-3-oxo-4-phenylbutanamide 80 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-2-[3-(trifluoromethyl)phenyl]acetamide 81 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-[2- (phenyloxy)ethyl]-1,3-benzothiazol-2-amine 82 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-(2-piperidin- 1-ylethyl)-1,3-benzothiazol-2-amine 83 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-methyl-N- (2-phenylethyl)-1,3-benzothiazol-2-amine 84 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-(2- pyrrolidin-1-ylethyl)-1,3-benzothiazol-2-amine 85 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-{[3- (trifluoromethyl)phenyl]methyl}-1,3-benzothiazol-2-amine 86 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-{2-[3- (trifluoromethyl)phenyl]ethyl}-1,3-benzothiazol-2-amine 87 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-[3-(trifluoromethyl)phenyl]propanediamide 88 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-[3-(trifluoromethyl)phenyl]acetamide 89 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N2-{[3-(trifluoromethyl)phenyl]methyl}glycinamide 90 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N2-(2-phenylethyl)glycinamide 91 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N2-{2-[3-(trifluoromethyl)phenyl]ethyl}glycinamide 92 benzyl-{[5-chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3- ylcarbamoyl]-methyl}-carbamic acid tert-butyl ester 93 N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N2-(phenylmethyl)glycinamide 94 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-[3,5-bis(trifluoromethyl)phenyl]acetamide 95 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzo- thiazol-2-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]acetamide 96 N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4- yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(2- phenylethyl)ethanediamide 97 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- (1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)ethanediamide 98 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- [(2-methyl-1,2,3,4-tetrahydroisoquinolin-1- yl)methyl]ethanediamide 99 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N2-methyl-N2-{[3-(trifluoromethyl)phenyl]methyl}glycinamide 100 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N2-methyl-N2-{2-[3-(trifluoromethyl)phenyl]ethyl}glycinamide 101 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N2-methyl-N2-(2-phenylethyl)glycinamide 102 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-4- (phenylmethyl)imidazolidin-2-one 103 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridazin-3-yl)-N′-(4- fluorophenyl)propanediamide 104 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-(2-chlorophenyl)propanediamide 105 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-(3-chlorophenyl)propanediamide 106 N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N2-methyl-N2-(phenylmethyl)glycinamide 107 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-(4-chlorophenyl)propanediamide 108 (2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2- [(methyloxy)imino]propanamide 109 (2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2- [(ethyloxy)imino]propanamide 110 (2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2- {[(phenylmethyl)oxy]imino}propanamide 111 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-1- (phenylmethyl)prolinamide 112 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-3-[(4- methylphenyl)sulfonyl]-4-(phenylmethyl)imidazolidin-2-one 113 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4- (phenylmethyl)imidazolidin-2-one 114 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4- (phenylmethyl)-4,5-dihydro-1,3-oxazol-2-amine 115 6,7-bis(methyloxy)-4-({4-[4-(phenylmethyl)piperazin-1- yl]phenyl}oxy)quinoline 116 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4- (phenylmethyl)piperazin-2-one 117 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2- (phenylmethyl)alaninamide 118 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-methyl- N2-(phenylmethyl)alaninamide 119 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2- (phenylmethyl)leucinamide 120 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-methyl- N2-(phenylmethyl)leucinamide 121 N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2- (phenylmethyl)valinamide 122 4-(6,7-dimethoxy-quinolin-4-ylamino)-N-(3-phenyl-propyl)- benzamide 123 4-benzyl-1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]- tetrahydro-pyrimidin-2-one 124 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-phenethyl-oxalamide 125 2-(Benzyl-methyl-amino)-N-[4-(6,7-dimethoxy-quinolin-4-yloxy)- phenyl]-3-methyl-butyramide (note: Alphabetic order of prefixes ignored while selecting parent chain) 126 N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-2-phenoxyimino- propionamide 127 2-Benzyloxyimino-N-[4-(6,7-dimethoxy-quinolin-4-yloxy)- phenyl]-2-phenyl-acetamide 128 4-[4-(4-Benzyl-piperidin-1-yl)-phenoxy]-6,7-dimethoxy-quinoline 129 N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2- isopropyl-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-oxalamide 130 N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2- ethyl-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-oxalamide 131 4-(4-{3-Chloro-5-[2-(4-fluoro-phenylcarbamoyl)-acetylamino]- pyridin-2-yloxy}-6-methoxy-quinolin-7-yloxymethyl)-piperidine- 1-carboxylic acid tert-butyl ester 132 N-{5-Chloro-6-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide 133 N-{5-Chloro-6-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide 134 N-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]- 3-fluoro-phenyl}-N′-phenethyl-oxalamide 135 N-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)- quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 136 N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin- p4-yloxy]-phenyl}-N′-henethyl-oxalamide 137 N-{4-[7-(2-Diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3- fluoro-phenyl}-N′-phenethyl-oxalamide 138 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-methyl-N′-phenethyl-oxalamide 139 N-{3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro- cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- phenethyl-oxalamide 140 N-{3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro- cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-N′- phenethyl-oxalamide 141 2-(3,4-Dihydro-1H-isoquinolin-2-yl)-N-{3-fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2- oxo-acetamide 142 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-2-oxo-2-(3-phenyl-pyrrolidin-1-yl)-acetamide 143 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-2-oxo-2-(2-phenyl-morpholin-4-yl)-acetamide 144 N-(2-Dimethylamino-2-phenyl-ethyl)-N′-{3-fluoro-4-[6-methoxy- 7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 145 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-oxo-2-phenyl-ethyl)-oxalamide 146 N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]- 2,2-difluoro-N′-(4-fluoro-phenyl)-malonamide 147 N-Benzyl-N′-{3-fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 148 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(2-fluoro-phenyl)-ethyl]-oxalamide 149 N-[2-(3-Chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 150 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(2-methoxy-phenyl)-ethyl]-oxalamide 151 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-pyridin-3-yl-ethyl)-oxalamide 152 N-Benzyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamide 153 N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 154 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(2-trifluoromethyl-phenyl)-ethyl]-oxalamide 155 N-[2-(2-Ethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 156 N-[2-(2,4-Dimethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 157 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(1S-phenyl-2-p-tolyl-ethyl)-oxalamide 158 N-[2-(4-Chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 159 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamic acid 160 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(3-fluoro-phenyl)-ethyl]-oxalamide 161 N-[2-(2-Chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 162 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(3-methoxy-phenyl)-ethyl]-oxalamide 163 N-(1,2-Diphenyl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 164 N-[2-(2,4-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 165 N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 166 N-[2-(4-Ethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 167 N-[2-(4-Ethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 168 N-[2-(4-Ethoxy-3-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide 169 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(4-phenoxy-phenyl)-ethyl]-oxalamide 170 N-[2-(3-Ethoxy-4-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide 171 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-pyridin-2-yl-ethyl)-oxalamide 172 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-pyridin-4-yl-ethyl)-oxalamide 173 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(4-fluoro-phenyl)-ethyl]-oxalamide 174 N-[2-(2-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 175 N-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide 176 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2R-phenyl-propyl)-oxalamide 177 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-indan-1-yl-oxalamide 178 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-isobutyl-oxalamide 179 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-(3-methyl-butyl)-oxalamide 180 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-(2R-phenyl-propyl)-oxalamide 181 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-(2-phenyl-propyl)-oxalamide 182 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-indan-2-yl-oxalamide 183 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(1R-phenyl-ethyl)-oxalamide 184 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(1S-phenyl-ethyl)-oxalamide 185 N-[2-(3-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 186 N-[2-(2,6-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 187 N-[2-(2,4-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 188 N-(2-Benzo[1,3]dioxol-5-yl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 189 N-[2-(3-Bromo-4-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide 190 N-[2-(3,5-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 191 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-o-tolyl-ethyl)-oxalamide 192 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-m-tolyl-ethyl)-oxalamide 193 N-[2-(3-Ethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 194 N-[2-(3,4-Dimethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 195 N-[2-(2,5-Dimethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 196 N-[2-(3-Chloro-4-propoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide 197 N-[2-(4-Butoxy-3-chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide 198 N-[2-(4-tert-Butyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 199 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(4-sulfamoyl-phenyl)-ethyl]-oxalamide 200 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]- oxalamide 201 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(3-hydroxy-4-methoxy-phenyl)-ethyl]- oxalamide 202 N-(2,4-Dichloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin- 4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 203 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(4-fluoro-2-trifluoromethyl-benzyl)-oxalamide 204 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(1-p-tolyl-ethyl)-oxalamide 205 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(3-fluoro-4-trifluoromethyl-benzyl)-oxalamide 206 N-(3-Chloro-4-fluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 207 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[1-(3-methoxy-phenyl)-ethyl]-oxalamide 208 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(1-naphthalen-2-yl-ethyl)-oxalamide 209 N-(4-Chloro-3-trifluoromethyl-benzyl)-N′-{3-fluoro-4-[6-methoxy- 7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 210 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(1-p-tolyl-ethyl)-oxalamide 211 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(6-trifluoromethyl-pyridin-3-ylmethyl)- oxalamide 212 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-methyl-benzyl)-oxalamide 213 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(3-methyl-benzyl)-oxalamide 214 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- fyloxy]-phenyl}-N′-(4-luoro-3-trifluoromethyl-benzyl)-oxalamide 215 N-(3,5-Dichloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin- 4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 216 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(1R,2,3,4-tetrahydro-naphthalen-1-yl)- oxalamide 217 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(1S,2,3,4-tetrahydro-naphthalen-1-yl)- oxalamide 218 N-Cyclopentyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 219 N-[1-(4-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 220 N-(2-Fluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 221 N-[2-(3,4-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 222 N-(4-Fluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 223 N-(2,3-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin- 4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 224 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-phenoxy-ethyl)-oxalamide 225 N-(2,2-Diphenyl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 226 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(4-methoxy-phenyl)-ethyl]-oxalamide 227 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-phenyl-propyl)-oxalamide 228 N-[2-(4-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 229 N-{4-[7-(1-Ethyl-piperidin-4-ylmethoxy)-6-methoxy-quinolin-4- yloxy]-3-fluoro-phenyl}-2-oxo-2-(2-phenyl-morpholin-4-yl)- acetamide 230 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(3-fluoro-5-trifluoromethyl-benzyl)-oxalamide 231 N-(3,5-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin- 4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 232 N-(2-Chloro-5-trifluoromethyl-benzyl)-N′-{3-fluoro-4-[6-methoxy- 7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 233 N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2- dimethylamino-2-phenyl-ethyl)-oxalamide 234 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(4-methoxy-benzyl)-oxalamide 235 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(4-trifluoromethyl-benzyl)-oxalamide 236 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(3-methoxy-benzyl)-oxalamide 237 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- tyloxy]-phenyl}-N′-(3-rifluoromethyl-benzyl)-oxalamide 238 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(3-trifluoromethoxy-benzyl)-oxalamide 239 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-methoxy-benzyl)-oxalamide 240 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-trifluoromethyl-benzyl)-oxalamide 241 N-(3-Chloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 242 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-trifluoromethoxy-benzyl)-oxalamide 243 N-(2-Chloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 244 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(4-trifluoromethoxy-benzyl)-oxalamide 245 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-(4-methoxy-benzyl)-oxalamide 246 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-(4-trifluoromethyl-benzyl)- oxalamide 247 N-{4-[7-(Azetidin-3-ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3- fluoro-phenyl}-N′-phenethyl-oxalamide 248 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-azetidin-3-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 249 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-hydroxy-2-phenyl-ethyl)-oxalamide 250 N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′- (2,4-difluoro-phenyl)-malonamide 251 N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′- (4-fluoro-phenyl)-N′-methyl-malonamide 252 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- pyloxy]-phenyl}-N′-(1R-henyl-propyl)-oxalamide 253 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(1R-phenyl-propyl)-oxalamide 254 N-(3,4-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin- 4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 255 N-(2,6-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin- 4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 256 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-[2-(4-fluoro-phenyl)-ethyl]- oxalamide 257 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′-phenyl-oxalamide 258 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(3-fluoro-phenyl)-oxalamide 259 N-(4-Chloro-3-fluoro-phenyl)-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 260 N-(3,4-Dimethoxy-phenyl)-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 261 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(3-methyl-butyl)-oxalamide 262 N-(3,3-Dimethyl-butyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 263 N-{5-Chloro-6-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin- 4-yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide 264 N-{5-Chloro-6-[6-methoxy-7-(3-morpholin-4-yl-propoxy)- quinolin-4-yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide 265 N-{5-Chloro-6-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin- 4-yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide 266 N-(4-Chloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 267 N-(3,5-Dimethoxy-benzyl)-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 268 N-(4-Butyl-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 269 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-p-tolyl-ethyl)-oxalamide 270 N-(3,5-Bis-trifluoromethyl-benzyl)-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 271 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-pyrazin-2-ylmethyl-oxalamide 272 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-pyridin-2-ylmethyl-oxalamide 273 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinazolin- 4-yloxy]-phenyl}-N′-phenethyl-oxalamide 274 N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinazolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 275 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-fluoro-3-trifluoromethyl-benzyl)-oxalamide 276 N-[2-(2-Bromo-6-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide 277 N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N-methyl- oxalamide 278 N-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide 279 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-fluoro-5-trifluoromethyl-benzyl)-oxalamide 280 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[1-(4-fluoro-phenyl)-ethyl]-oxalamide 281 N-(1S-Benzyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide 282 N-{3-Fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5- ylmethoxy)-quinazolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 283 N-[2-(4-Amino-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 284 2-(4-Benzyl-piperidin-1-yl)-N-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2-oxo- acetamide 285 N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-N′-(4-fluoro- phenyl)-malonamide 286 N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′- (3-fluoro-phenyl)-malonamide 287 N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′- phenyl-malonamide 288 N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′- (4-fluoro-phenyl)-2,2-dimethyl-malonamide 289 N-Ethyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamide 290 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-isopropyl-oxalamide 291 N-Butyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-oxalamide 292 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-methoxy-ethyl)-oxalamide 293 N-Cyclopropylmethyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 294 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-morpholin-4-yl-ethyl)-oxalamide 295 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-2-oxo-2-pyrrolidin-1-yl-acetamide 296 N-Ethyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N-methyl-oxalamide and a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, solvate, or hydrate thereof.

TABLE 3c Additional Representative c-MET Inhibitors Entry Name 1 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 2 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 3 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-(phenylmethyl)cyclopropane-1,1-dicarboxamide 4 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-phenylcyclopropane-1,1-dicarboxamide 5 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 6 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-1- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 7 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-1- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane-1,1-dicarboxamide 8 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)-N′-(2-phenylethyl)cyclopropane-1,1-dicarboxamide 9 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-methylpyridin-3- yl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 10 N-{4-[(7-chloroquinolin-4-yl)oxy]-3-fluorophenyl}-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 11 N-{4-[(7-chloroquinolin-4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 12 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 13 N-(4-{[6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 14 N-(4-{[6,7-bis(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)cyclopropane-1,1-dicarboxamide 15 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 16 N-{5-chloro-6-[(6-(methyloxy)-7-{[(1-methylpiperidin-4- yl)methyl]oxy}quinolin-4-yl)oxy]pyridin-3-yl}-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 17 N-[5-chloro-6-({6-(methyloxy)-7-[(piperidin-4- ylmethyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 18 N-[5-chloro-6-({6-(methyloxy)-7-[(phenylmethyl)oxy]quinolin-4- yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 19 N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 20 N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1- dicarboxamide 21 N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4- yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 22 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-methylphenyl)-N′- (4-fluorophenyl)cyclopropane-1,1-dicarboxamide 23 N-(4-fluorophenyl)-N′-[2-methyl-6-({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)pyridin-3- yl]cyclopropane-1,1-dicarboxamide 24 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)cyclopropane-1,1-dicarboxamide 25 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloro-2-methyl- pyridin-3-yl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 26 N-[3-fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 27 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3,5-difluorophenyl)- N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 28 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,5-difluorophenyl)- N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 29 N-[3-fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 30 N-{3-fluoro-4-[(6-(methyloxy)-7-(2-methyl octahydrocyclo- penta[c]pyrrol-5-ylmethoxy)quinazolin-4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 31 N-{3-fluoro-4-[(7-(methyloxy)-6-{[(1-methylpiperidin-4- yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 32 N-[5-fluoro-2-methyl-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 33 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,3,5-trifluoro- phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 34 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-2-methyl- phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 35 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-chloro-5-methyl- phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 36 N-(3-fluoro-4-{[6-hydroxy-7-(methyloxy)quinolin-4-yl]oxy}phen- yl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 37 N-(4-fluorophenyl)-N′-[2-methyl-4-({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]cyclopropane- 1,1-dicarboxamide 38 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 39 N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1- yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 40 N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4- yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 41 N-(4-fluorophenyl)-N′-[4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]cyclopropane-1,1- dicarboxamide 42 N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 43 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-chloro-5- fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 44 N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 45 N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7-bis(methyl- oxy)quinazolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide 46 N-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 47 N-(3-fluoro-4-{[2-(methylamino)-6,7-bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 48 (1S,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1-dicarboxamide 49 (1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1-dicarboxamide 50 N-(4-{[6-{[3-(diethylamino)propyl]oxy}-7-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 51 N-(4-{[6-{[2-(diethylamino)ethyl]oxy}-7-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 52 1,1-dimethylethyl 4-(3-{[4-[(2-fluoro-4-{[(1-{[(4-fluorophen- yl)amino]carbonyl}cyclopropyl)carbonyl]amino}phenyl)oxy]-6- (methyloxy)quinolin-7-yl]oxy}propyl)piperazine-1-carboxylate 53 (1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1-dicarboxamide 54 (1R,2R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyl- oxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1-dicarboxamide 55 N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin- 4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 56 N-(4-{[7-{[3-(4-acetylpiperazin-1-yl)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 57 1,1-dimethylethyl 4-(3-{[4-[(2-fluoro-4-{[((1R,2R)-1-{[(4-fluoro- phenyl)amino]carbonyl}-2-methylcyclopropyl)carbon- yl]amino}phenyl)oxy]-6-(methyloxy)quinolin-7- yl]oxy}propyl)piperazine-1-carboxylate 58 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4- fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide 59 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4- fluorophenyl)azetidine-3,3-dicarboxamide 60 (1R,2S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin- 1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1-dicarboxamide 61 (1R,2R)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin- 1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1-dicarboxamide 62 (1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1-dicarboxamide 63 N-(3-fluoro-4-{[7-({3-[4-(1-methylethyl)piperazin-1- yl]propyl}oxy)-6-(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide 64 N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin- 4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 65 (1R,2R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 66 (1R,2R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 67 (1R,2S)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 68 (1R,2S)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 69 N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1- dicarboxamide 70 (1R,2S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1-dicarboxamide 71 (1R,2R,3S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3- dimethylcyclopropane-1,1-dicarboxamide 72 (1R,2R,3S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- methylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 73 (1R,2R,3S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3- dimethylcyclopropane-1,1-dicarboxamide 74 (1R,2R,3S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- methylpiperazin-1-yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′- (4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 75 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane-1,1-dicarboxamide 76 (2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3- dimethylcyclopropane-1,1-dicarboxamide 77 (2R,3R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- f(methyloxy)quinolin-4-yl]oxy}-3-luorophenyl)-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 78 N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2- dimethylcyclopropane-1,1-dicarboxamide 79 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,2- dimethylcyclopropane-1,1-dicarboxamide 80 (1R,2R,3S)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 81 N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2- dimethylcyclopropane-1,1-dicarboxamide 82 (1R,2R,3S)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 83 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,2- dimethylcyclopropane-1,1-dicarboxamide 84 N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2- dimethylcyclopropane-1,1-dicarboxamide 85 N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin- 4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2- dimethylcyclopropane-1,1-dicarboxamide 86 N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin- 4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1- dicarboxamide 87 N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1- yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclobutane-1,1-dicarboxamide 88 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1- ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane-1,1-dicarboxamide 89 (2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3- dimethylcyclopropane-1,1-dicarboxamide 90 N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1- dicarboxamide 91 N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1- yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclobutane-1,1-dicarboxamide 92 (1R,2R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- (methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 93 (1R,2R)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin- 1-yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)- 2-methylcyclopropane-1,1-dicarboxamide 94 (2R,3R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- (methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 95 (2R,3R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- (methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 96 (1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1- ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1-dicarboxamide 97 (2R,3R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- f(methyloxy)quinolin-4-yl]oxy}-3-luorophenyl)-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 98 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[(4- fluorophenyl)methyl]cyclopropane-1,1-dicarboxamide 99 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(2- morpholin-4-ylethyl)cyclopropane-1,1-dicarboxamide 100 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2- (piperidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 101 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2- (pyrrolidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 102 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3- (morpholin-4-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 103 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2- (morpholin-4-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 104 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′- phenylcyclopropane-1,1-dicarboxamide 105 N-[3-(aminomethyl)phenyl]-N′-(4-{[6,7-bis(methyloxy)quinolin-4- yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide 106 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3- (piperidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 107 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3- (pyrrolidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, solvate, or hydrate thereof.

TABLE 4 Representative EGFR and/or VEGFR Inhibitors Entry Name 1 N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1- methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 2 N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1- methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 3 7-({[(3aR,5r,6aS)-2-acetyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-N-(4-bromo-3-chloro-2-fluorophenyl)-6- (methyloxy)quinazolin-4-amine 4 N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7- {[(3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5- ylmethyl]oxy}quinazolin-4-amine 5 ethyl (3aR,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]- 6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro- cyclopenta[c]pyrrole-2(1H)-carboxylate 6 N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7- ({[(3aR,5r,6aS)-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)quinazolin-4-amine 7 N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-ethylocta- hydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 8 N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)- 2-(2-methylpropyl)octahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)quinazolin-4-amine 9 N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 10 N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 11 N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 12 N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 13 N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 14 N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 15 N-(3,4-dichlorophenyl)-7-({[(3aR,5s,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 16 N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2- ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 17 N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7- ({[(3aR,5r,6aS)-2-(2-(methylpropyl)octahydrocyclopenta[c]pyrrol- 5-yl]methyl}oxy)quinazolin-4-amine 18 N-(4-bromo-2,3-dichlorophenyl)-7-{[(3R,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 19 N-(4,5-dichloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 20 N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 21 N-(3-chloro-2,4-difluorophenyl)-7-{[(3R,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 22 N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 23 N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 24 N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 25 N-(3,4-dichlorophenyl)-7-[(hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3-ylmethyl)oxy]-6-(methyloxy)quinazolin-4-amine 26 N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 27 N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 28 N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 29 N-(3,4-dichloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 30 N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 31 N-(3,4-dichlorophenyl)-7-{[(3R,8aR)-hexahydro-1H-pyrrolo[2,1- c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 32 N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H- pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 33 N-(3,4-dichlorophenyl)-7-{[(3S,8aR)-hexahydro-1H-pyrrolo[2,1- c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 34 N-(3,4-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1- c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 35 N-(3,4-dichlorophenyl)-7-{[(3R,8aS)-hexahydro-1H-pyrrolo[2,1- c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 36 N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H- pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 37 N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H- pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 38 N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,8aS)-hexahydro-1H- pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 39 N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H- pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 40 N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H- pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine 41 1,4:3,6-dianhydro-5-({[4-[(4-bromo-5-chloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-5- deoxy-2-O-methyl-D-xylo-hexitol 42 1,4:3,6-dianhydro-5-deoxy-5-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-2-O-methyl-D-glucitol 43 1,4:3,6-dianhydro-5-deoxy-5-({[4-[(3,4-dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2- O-methyl-D-xylo-hexitol 44 1,4:3,6-dianhydro-5-({[4-[(4-bromo-3-chloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-5- deoxy-2-O-methyl-D-xylo-hexitol 45 1,4:3,6-dianhydro-5-({[4-[(3-chloro-2,4-difluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D- xylo-hexitol 46 1,4:3,6-dianhydro-5-({[4-[(4-bromo-2,3-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D- glucitol 47 1,4:3,6-dianhydro-2-deoxy-2-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-5-O-methyl-D-threo- hexitol 48 1,4:3,6-dianhydro-5-deoxy-5-({[4-[(4,5-dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2- O-methyl-D-glucitol 49 (3S,9aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro-2H-pyrido[1,2- a]pyrazin-1(6H)-one 50 (3S,9aR)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro-2H-pyrido[1,2- a]pyrazin-1(6H)-one 51 (3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2- a]pyrazin-1(2H)-one 52 (3S,8aR)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2- a]pyrazin-1(2H)-one 53 (3S,8aS)-3-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2- a]pyrazin-1(2H)-one 54 (3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-2- methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one 55 N-(3,4-dichlorophenyl)-7-({2-[(8-methyl-8-azabicyclo[3.2.1]oct-3- yl)amino]ethyl}oxy)-6-(methyloxy)quinazolin-4-amine 56 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro-1H- [1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy}quinazolin-4-amine 57 N-(3,4-dichlorophenyl)-7-{[2-(8-methyl-8-azabicyclo[3.2.1]oct-3- yl)ethyl]oxy}-6-(methyloxy)quinazolin-4-amine 58 N-(3,4-dichlorophenyl)-7-{[(8-methyl-8-azabicyclo[3.2.1]oct-3- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 59 N-(3,4-dichlorophenyl)-7-{[(3aR,6aS)-2-methyloctahydro- cyclopenta[c]pyrrol-5-yl]oxy}-6-(methyloxy)quinazolin-4-amine 60 N-(3,4-dichlorophenyl)-7-[(8-methyl-8-azabicyclo[3.2.1]oct-3- yl)oxy]-6-(methyloxy)quinazolin-4-amine 61 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-5-chloro-2-fluoro- phenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 62 1,4:3,6-dianhydro-2-O-[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 63 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chloro-2-fluorophen- yl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 64 1,4:3,6-dianhydro-2-O-methyl-5-O-{6-(methyloxy)-4-[(2,3,4- trichlorophenyl)amino]quinazolin-7-yl}-L-iditol 65 1,4:3,6-dianhydro-5-O-[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-O-methyl-D-xylo-hexitol 66 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-2,3-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 67 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-L-sorbose ethylene glycol acetal 68 1,4:3,6-dianhydro-2-O-[4-[(3-chloro-2,4-difluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 69 1,4:3,6-dianhydro-2-O-[4-[(4,5-dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 70 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-(difluoromethyl)-L-iditol 71 1,4:3,6-dianhydro-2-O-[4-[(3-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 72 1,4:3,6-dianhydro-2-O-[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 73 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 74 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-ethyl-L-iditol 75 1,4:3,6-dianhydro-2-O-[4-[(3-bromo-2-methylphenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 76 1,4:3,6-dianhydro-2-O-[4-[(3-chloro-2-methylphenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 77 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-deoxy-D-xylo-hexitol 78 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-D-glucitol 79 methyl 3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-O-methyl-alpha-L-idofuranoside 80 3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-1,2-O-(1-methylethylidene)-beta-L- xylo-hexofuranose 81 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-deoxy-5-methylidene-D-xylo-hexitol 82 methyl 3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-O-methyl-beta-L-idofuranoside 83 N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-[(octahydro-2H- quinazolin-3-ylmethyl)oxy]quinazolin-4-amine 84 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,3,4- trifluorophenyl)amino]quinazolin-7-yl}-D-iditol 85 1,4:3,6-dianhydro-5-O-[4-[(2-chloro-4-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 86 1,4:3,6-dianhydro-5-O-[4-[(2-bromo-4-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 87 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,6-difluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 88 1,4:3,6-dianhydro-5-O-[4-[(3-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 89 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[4-fluoro-3-(trifluoro- methyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol 90 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,4-difluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 91 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,5-difluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 92 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,3-difluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 93 1,4:3,6-dianhydro-5-O-[4-[(5-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 94 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,5-difluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 95 1,4:3,6-dianhydro-5-O-[4-[(3-chloro-4-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 96 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-2-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 97 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-dichloro-2-fluoro- phenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 98 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-5-chloro-2-fluorophen- yl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 99 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,4,5- trifluorophenyl)amino]quinazolin-7-yl}-D-iditol 100 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,4,6- trifluorophenyl)amino]quinazolin-7-yl}-D-iditol 101 1,4:3,6-dianhydro-5-O-[4-({4-[(4-chlorophenyl)oxy]-3,5-difluoro- phenyl}amino)-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D- iditol 102 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro-2-fluorophen- yl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 103 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-2,3-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 104 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro-5-fluorophen- yl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 105 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(4,5-dichloro-2-fluorophen- yl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 106 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,3,4- trichlorophenyl)amino]quinazolin-7-yl}-D-iditol 107 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(3,4,5- trichlorophenyl)amino]quinazolin-7-yl}-D-iditol 108 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 109 1,4:3,6-dianhydro-5-O-[4-[(4-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 110 1,4:3,6-dianhydro-5-O-[4-[(3-chloro-2-methylphenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 111 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-difluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 112 1,4:3,6-dianhydro-5-O-[4-[(2-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 113 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-[(2- fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-D-iditol 114 1,4:3,6-dianhydro-5-O-[4-[(3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 115 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-[(4- fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-D-iditol 116 1,4:3,6-dianhydro-5-O-[4-[(4-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 117 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 118 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,5-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 119 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 120 1,4:3,6-dianhydro-5-O-[4-[(2-bromo-4,6-difluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 121 1,4:3,6-dianhydro-5-O-[4-{[4-chloro-3-(trifluoromethyl)phen- yl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 122 1,4:3,6-dianhydro-5-O-[4-{[2-chloro-5-(trifluoromethyl)phen- yl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 123 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[2-fluoro-3-(trifluoro- methyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol 124 1,4:3,6-dianhydro-5-O-[4-{[2-bromo-5-(trifluoromethyl)phen- yl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 125 1,4:3,6-dianhydro-5-O-[4-{[2-bromo-4-(trifluoromethyl)phen- yl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 126 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[4-fluoro-2-(trifluoro- methyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol 127 1,4:3,6-dianhydro-5-O-[4-{[3-bromo-5-(trifluoromethyl)phen- yl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 128 1,4:3,6-dianhydro-5-O-[4-[(2-bromophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 129 1,4:3,6-dianhydro-5-O-[4-[(3-bromophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 130 1,4:3,6-dianhydro-5-O-[4-[(4-bromophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 131 1,4:3,6-dianhydro-5-O-[4-[(3-bromo-4-methylphenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 132 1,4:3,6-dianhydro-5-O-[4-[(5-chloro-2-methylphenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 133 1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,5-dimethylphenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 134 1,4:3,6-dianhydro-5-O-[4-{[2,5-bis(methyloxy)phenyl]amino}-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 135 1,4:3,6-dianhydro-5-O-[4-{[5-chloro-2,4-bis(methyloxy)phen- yl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 136 1,4:3,6-dianhydro-5-O-[4-{[4-chloro-2,5-bis(methyloxy)phen- yl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 137 1,4:3,6-dianhydro-5-O-[4-[(3-chloro-2,4-difluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 138 N-(3,4-dichlorophenyl)-7-[({5-[(dimethylamino)methyl]-1,2,4- oxadiazol-3-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 139 N-(3,4-dichlorophenyl)-7-[({3-[(dimethylamino)methyl]-1,2,4- oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 140 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(4-methylpiperazin- o1-yl)methyl]-1,2,4-xadiazol-5-yl}methyl)oxy]quinazolin-4-amine 141 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-4-yl-1,2,4- oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 142 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-4- yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 143 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(morpholin-4- ylmethyl)-1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-amine 144 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2- ylmethyl)oxy]quinazolin-4-amine 145 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-2-yl-1,2,4- oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 146 N-(3,4-dichlorophenyl)-7-[({2-[(dimethylamino)methyl]-1,3- thiazol-4-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 147 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4- (phenylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 148 1,1-dimethylethyl 2-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholine-4-carboxylate 149 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(morpholin-4- ylmethyl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 150 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(4-methylpiperazin- 1-yl)methyl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 151 N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}- 6-(methyloxy)quinazolin-4-amine 152 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(1,4-oxazepan-2- ylmethyl)oxy]quinazolin-4-amine 153 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-3-yl-1,2,4- oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 154 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-2- yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 155 N-(3,4-dichlorophenyl)-7-{[(4-methyl-1,4-oxazepan-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 156 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-3- yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 157 N-(3,4-dichlorophenyl)-7-({[5-(1,1-dimethylethyl)-1,2,4-oxadiazol- 3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 158 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-phenyl-1,3-thiazol-4- yl)methyl]oxy}quinazolin-4-amine 159 7-[(2,1,3-benzothiadiazol-4-ylmethyl)oxy]-N-(3,4-dichlorophenyl)- 6-(methyloxy)quinazolin-4-amine 160 N-(3,4-dichlorophenyl)-7-{[(5-methylisoxazol-3-yl)methyl]oxy}-6- (methyloxy)quinazolin-4-amine 161 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-methyl-4- phenylisoxazol-3-yl)methyl]oxy}quinazolin-4-amine 162 7-[(1,3-benzothiazol-2-ylmethyl)oxy]-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine 163 7-[(2,1,3-benzoxadiazol-5-ylmethyl)oxy]-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine 164 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(2-thienyl)-1,3- thiazol-4-yl]methyl}oxy)quinazolin-4-amine 165 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(1-phenyl-1H-pyrazol-4- yl)methyl]oxy}quinazolin-4-amine 166 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[3-(trifluorometh- yl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine 167 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[4-(trifluorometh- yl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine 168 7-({[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 169 7-({[6-bromo-2-(methyloxy)naphthalen-1-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 170 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(1,3-thiazol-4- ylmethyl)oxy]quinazolin-4-amine 171 7-{[(6-chloropyridin-3-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine 172 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(pyridin-4-ylmethyl)oxy]quinazolin-4-amine 173 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-methyl-1,3-thiazol-4- yl)methyl]oxy}quinazolin-4-amine 174 7-{[(6-chloro-4H-1,3-benzodioxin-8-yl)methyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 175 7-{[(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)methyl]oxy}-N- (3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 176 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[1-methyl-3-(trifluoro- methyl)-1H-thieno[2,3-c]pyrazol-5-yl]methyl}oxy)quinazolin-4- amine 177 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-phenylisoxazol-5- yl)methyl]oxy}quinazolin-4-amine 178 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2,4,6- trimethylphenyl)methyl]oxy}quinazolin-4-amine 179 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(pyridin-3- ylmethyl)oxy]quinazolin-4-amine 180 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[4-(methyl- oxy)phenyl]isoxazol-5-yl}methyl)oxy]quinazolin-4-amine 181 N-(3,4-dichlorophenyl)-7-({[5-[(2,4-dichlorophenyl)oxy]-1-methyl- 3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 182 7-[(cyclopropylmethyl)oxy]-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine 183 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(tetrahydrofuran-2- ylmethyl)oxy]quinazolin-4-amine 184 7-(cyclopentyloxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine 185 7-[(2-cyclohexylethyl)oxy]-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine 186 7-[(cyclohexylmethyl)oxy]-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine 187 7-[(cyclobutylmethyl)oxy]-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine 188 N-(3,4-dichlorophenyl)-7-{[2-(1,3-dioxolan-2-yl)ethyl]oxy}-6- (methyloxy)quinazolin-4-amine 189 N-(3,4-dichlorophenyl)-7-{[2-(1,3-dioxan-2-yl)ethyl]oxy}-6- (methyloxy)quinazolin-4-amine 190 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-morpholin-4- ylethyl)oxy]quinazolin-4-amine 191 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-pyrrolidin-1- ylethyl)oxy]quinazolin-4-amine 192 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-piperidin-1- ylethyl)oxy]quinazolin-4-amine 193 2-(2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}ethyl)-1H-isoindole-1,3(2H)-dione 194 methyl 6-O-[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-alpha-D-glucopyranoside 195 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-morpholin-4-yl-2- oxoethyl)oxy]quinazolin-4-amine 196 1,1-dimethylethyl 2-[3-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5- yl]piperidine-1-carboxylate 197 1,1-dimethylethyl 4-[3-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5- yl]piperidine-1-carboxylate 198 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(4-pyrrolidin-1- ylphenyl)-1,3-thiazol-2-yl]methyl}oxy)quinazolin-4-amine 199 N-(3,4-dichlorophenyl)-7-[({4-[4-(diethylamino)phenyl]-1,3- thiazol-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 200 5-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)-1,3-thiazol-4-yl]-2-hydroxybenzamide 201 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-3-yl-1,3- thiazol-2-yl)methyl]oxy}quinazolin-4-amine 202 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-2-yl-1,3- thiazol-2-yl)methyl]oxy}quinazolin-4-amine 203 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-4-yl-1,3- thiazol-2-yl)methyl]oxy}quinazolin-4-amine 204 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-morpholin-4-yl-1,3- thiazol-4-yl)methyl]oxy}quinazolin-4-amine 205 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-morpholin-4-yl-1,2,4- oxadiazol-5-yl)methyl]oxy}quinazolin-4-amine 206 N-(3,4-dichlorophenyl)-7-({[3-(dimethylamino)-1,2,4-oxadiazol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 207 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(4-methylpiperazin- 1-yl)methyl]-1,3-thiazol-2-yl}methyl)oxy]quinazolin-4-amine 208 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahy- dro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine 209 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(morpholin-4- ylmethyl)-1,3-thiazol-2-yl]methyl}oxy)quinazolin-4-amine 210 N-(3,4-dichlorophenyl)-7-[({4-[(4-methyl-1,4-diazepan-1-yl)meth- yl]-1,3-thiazol-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 211 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-{[(phenylmethyl)ox- y]methyl}-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 212 N-(3,4-dichlorophenyl)-7-{[(4-ethylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4-amine 213 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-4-yl-1,3- thiazol-4-yl)methyl]oxy}quinazolin-4-amine 214 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-4- yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 215 1,1-dimethylethyl 4-[5-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-3- yl]piperazine-1-carboxylate 216 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-piperazin-1-yl-1,2,4- oxadiazol-5-yl)methyl]oxy}quinazolin-4-amine 217 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(4-methylpiperazin-1- yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-amine 218 N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-2-yl)-1,2,4- oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 219 N-(3,4-dichlorophenyl)-7-({[3-(4-ethylpiperazin-1-yl)-1,2,4- oxadiazol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 220 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[4-(methyl- oxy)phenyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine 221 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[4-(trifluoro- methyl)phenyl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 222 7-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 223 N-(3,4-dichlorophenyl)-7-({[5-(3,5-dimethylisoxazol-4-yl)-1,2,4- yoxadiazol-3-l]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 224 7-{[(5-chloro-1-benzothien-3-yl)methyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 225 N-(3,4-dichlorophenyl)-7-[({3-[4-(1,1-dimethylethyl)phenyl]-1,2,4- oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 226 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[2-(methyl- oxy)phenyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine 227 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(4-methylphenyl)- 1,3,4-oxadiazol-2-yl]methyl}oxy)quinazolin-4-amine 228 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[1-(phenylmethyl)-1H- yimidazol-2-l]methyl}oxy)quinazolin-4-amine 229 N-(3,4-dichlorophenyl)-7-({[3-(2,6-dichlorophenyl)-5-methyl- isoxazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 230 N-(3,4-dichlorophenyl)-7-{[(6-fluoro-4H-1,3-benzodioxin-8- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 231 7-{[(3,5-dibromophenyl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- 4(methyloxy)quinazolin--amine 232 N-(3,4-dichlorophenyl)-7-{[(2,6-difluorophenyl)methyl]oxy}-6- (methyloxy)quinazolin-4-amine 233 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(pyridin-2-ylsulfo- nyl)methyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine 234 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-phenyl-1,2,4- oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 235 7-({[4-chloro-2-(trifluoromethyl)quinolin-6-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 236 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(1-methylpyrrolidin-2- yl)ethyl]oxy}quinazolin-4-amine 237 N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-4-yl)-1,2,4- oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 238 N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-3-yl)-1,2,4- oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 239 N-(3,4-dichlorophenyl)-7-({[2-(dimethylamino)-1,3-thiazol-4- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 240 N-(3,4-dichlorophenyl)-7-{[(4-ethyl-1,4-oxazepan-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 241 N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-4-yl)-1,3-thiazol-4- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 242 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(2S)-pyrrolidin-2- yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine 243 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(2S)-pyrrolidin-2- yl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 244 [4-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)-1,3-thiazol-2-yl]methyl benzoate 245 [4-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)-1,3-thiazol-2-yl]methanol 246 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-methyl-4,5,6,7- tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}quinazolin- 4-amine 247 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(4S)-1,3-thiazolidin- 4-yl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 248 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-2-yl-1,3- thiazol-4-yl)methyl]oxy}quinazolin-4-amine 249 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-2- yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 250 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-3-yl-1,3- thiazol-4-yl)methyl]oxy}quinazolin-4-amine 251 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-3- yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 252 N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-2-yl)-1,3-thiazol-4- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 253 N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-3-yl)-1,3-thiazol-4- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 254 N-(3,4-dichlorophenyl)-7-[({3-[(2S)-1-ethylpyrrolidin-2-yl]-1,2,4- oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 255 N-(3,4-dichlorophenyl)-7-[({2-[(2S)-1-ethylpyrrolidin-2-yl]-1,3- thiazol-4-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 256 N-(3,4-dichlorophenyl)-7-{[(5-ethyl-4,5,6,7- tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4-amine 257 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propyl-1,4-oxazepan- 2-yl)methyl]oxy}quinazolin-4-amine 258 7-({[4-(cyclopropylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 259 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[2-(methyloxy)ethyl]- 1,4-oxazepan-2-yl}methyl)oxy]quinazolin-4-amine 260 N-(3,4-dichlorophenyl)-7-({[4-(1-methylethyl)-1,4-oxazepan-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 261 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperazin-1-yl-1,3- thiazol-4-yl)methyl]oxy}quinazolin-4-amine 262 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-pyrrolidin-2-yl-1,2,4- oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 263 N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpyrrolidin-2-yl)-1,2,4- oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 264 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(2S)-1- methylpyrrolidin-2-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]quinazolin-4-amine 265 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(2S)-1-methyl- pyrrolidin-2-yl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 266 N-(3,4-dichlorophenyl)-7-({[2-(4-ethylpiperazin-1-yl)-1,3-thiazol-4- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 267 N-(3,4-dichlorophenyl)-7-{[(1,4-dimethylpiperazin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 268 7-{[(4-cyclopentylmorpholin-2-yl)methyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 269 N-(3,4-dichlorophenyl)-7-({[4-(1-methylethyl)morpholin-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 270 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(3- phenylpropyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 271 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[2- (methyloxy)ethyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine 272 ethyl 2-[2-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]propanoate 273 N-(3,4-dichlorophenyl)-7-{[(4-hex-5-en-1-ylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 274 2-({2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyl- oxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]ethyl}oxy)ethanol 275 methyl 3-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyl- oxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]propanoate 276 6-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin-4-yl]hexanenitrile 277 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(tetrahydro-2H- pyran-2-ylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 278 4-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin-4-yl]butanenitrile 279 N-(3,4-dichlorophenyl)-7-[({4-[(4-fluorophenyl)methyl]morpholin- 2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 280 methyl 5-[2-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]pentanoate 281 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-oct-7-en-1- ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 282 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propylmorpholin-2- yl)methyl]oxy}quinazolin-4-amine 283 6-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin-4-yl]hexan-1-ol 284 7-{[(4-acetylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)- 6-(methyloxy)quinazolin-4-amine 285 7-({[4-(cyclopropylmethyl)morpholin-2-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 286 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-prop-2-yn-1- ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 287 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-4- ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 288 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(pyridin-2- ylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 289 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pent-2-yn-1- ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 290 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(4-methylpiperazin-1- yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 291 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpyrrolidin- 2-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 292 N-(3-chloro-4-fluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 293 7-{[(4-butyl-1,4-oxazepan-2-yl)methyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 294 (3,4-dichlorophenyl)[7-(methyloxy)-6-({[4-(2-methylpropyl)-1,4- oxazepan-2-yl]methyl}oxy) quinazolin-4-amine 295 7-{[(4-acetyl-1-ethylpiperazin-2-yl)methyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 296 (3,4-dichlorophenyl)(6-(methyloxy)-7-{[(4-pentyl-1,4-oxazepan-2- yl)methyl]oxy}quinazolin-4-amine 297 (3,4-dichlorophenyl)[6-(methyloxy)-7-({[4-(tetrahydro-2H-pyran-2- ylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)quinazolin-4-amine 298 (3,4-dichlorophenyl)[6-(methyloxy)-7-({[4-(3-thienylmethyl)-1,4- oxazepan-2-yl]methyl}oxy) quinazolin-4-amine 299 N-[4-chloro-2,5-bis(methyloxy)phenyl]-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 300 N-(3-bromo-2-methylphenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 301 7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)-N-(3,4,5- trichlorophenyl)quinazolin-4-amine 302 N-(3-chloro-2-methylphenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 303 N-(3,4-dichlorophenyl)-7-{[(4-ethanimidoyl-1,4-oxazepan-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 304 N-(4-bromo-2-fluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 305 N-(5-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 306 N-(4-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 307 N-(2,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}- 6-(methyloxy)quinazolin-4-amine 308 N-(2,4-dibromophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}- 6-(methyloxy)quinazolin-4-amine 309 7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)-N-(2,3,4- trichlorophenyl)quinazolin-4-amine 310 N-(3,4-dichlorophenyl)-7-{[(1-ethyl-4-methylpiperazin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 311 N′-cyano-2-({[4-[(3,4-dicholorophenyl)amino]-6-(methylox- y)quinazolin-7-yl]oxy}methyl)morpholine-4-carboximidamide 312 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(pyrrolidin-1- ylmethyl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 313 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(tetrahydro-2H- pyran-4-yl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 314 N-(3,4-dichlorophenyl)-7-({[4-(2-ethylbutyl)morpholin-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 315 7-({[4-(cyclohexylmethyl)morpholin-2-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 316 2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin-4-yl]ethanol 317 7-{[(4-but-2-yn-1-ylmorpholin-2-yl)methyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 318 7-{[(4-cyclobutylmorpholin-2-yl)methyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 319 N-(3,4-dichlorophenyl)-7-[({4-[2-(1,3-dioxolan-2-yl)ethyl]morph- olin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 320 7-({[(4-(2-cyclohexylethyl)morpholin-2-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 321 N-(3,4-dichlorophenyl)-7-[({4-[2-(1,3-dioxan-2-yl)ethyl]morpholin- 2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 322 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pent-4-en-1- ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 323 N-(3,4-dichlorophenyl)-7-[({4-[(2R)-2-methylbutyl]morpholin-2- yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 324 N-(3,4-dichlorophenyl)-7-({[4-(4-fluorobutyl)morpholin-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 325 3-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin-4-yl]butan-2-one 326 1-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin-4-yl]butan-2-one 327 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pentylmorpholin-2- yl)methyl]oxy}quinazolin-4-amine 328 N-(3,4-dichlorophenyl)-7-{[(4-hexylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4-amine 329 N-(3,4-dichlorophenyl)-7-{[(4-heptylmorpholin-2-yl)methyl]oxy}- 6-(methyloxy)quinazolin-4-amine 330 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-octylmorpholin-2- yl)methyl]oxy}quinazolin-4-amine 331 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2- phenylethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 332 7-{[(4-butylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine 333 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-prop-2-en-1- ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 334 2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin-4-yl]-1-phenylethanone 335 N-(3,4-dichlorophenyl)-7-({[4-(2-fluoroethyl)morpholin-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 336 N-(3,4-dichlorophenyl)-7-({[4-(3-methylbut-2-en-1-yl)morpholin-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 337 7-[({4-[(2E)-3-bromoprop-2-en-1-yl]morpholin-2-yl}methyl)oxy]- N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 338 2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin-4-yl]acetamide 339 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[3-(tetrahydro-2H- pyran-2-yloxy)propyl]-1,4-oxazepan-2-yl}methyl)oxy]quinazolin-4- amine 340 N-(3,4-dichlorophenyl)-7-({[4-(3-methylbutyl)-1,4-oxazepan-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 341 7-({[4-(cyclohexylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)-4-[(3,4- dichlorophenyl)methyl]-6-(methyloxy)quinazoline 342 7-({[4-(2-cyclohexylethyl)-1,4-oxazepan-2-yl]methyl}oxy)-4-[(3,4- dichlorophenyl)methyl]-6-(methyloxy)quinazoline 343 N-(3,4-dichlorophenyl)-7-({[4-(2-ethylbutyl)-1,4-oxazepan-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 344 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(methylsulfonyl)-1,4- oxazepan-2-yl]methyl}oxy)quinazolin-4-amine 345 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(1-methylpiperidin-4- yl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 346 N-(3-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 347 N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methylox- y)quinazolin-7-yl]oxy}methyl)-1,4-oxazepane-4-carboximidamide 348 N-(3-bromo-4-methylphenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 349 N-(3,4-dichlorophenyl)-7-{[(1,4-diethylpiperazin-2-yl)methyl]oxy}- 6-(methyloxy)quinazolin-4-amine 350 4-({[4-[(4-bromo-2-fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-N′-cyanopiperidine-1-carboximidamide 351 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4- (methylsulfonyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 352 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(phenyl- methyl)sulfonyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine 353 N-(3,4-dichlorophenyl)-7-[({4-[(4-fluorophenyl)sulfo- nyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 354 N-(3,4-dichlorophenyl)-7-({[4-(ethylsulfonyl)morpholin-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 355 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(phenyl- sulfonyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 356 7-[({4-[(3-chloropropyl)sulfonyl]morpholin-2-yl}methyl)oxy]-N- (3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 357 7-({[4-(butylsulfonyl)morpholin-2-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 358 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(4-methylphen- yl)sulfonyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine 359 N-(3,4-dichlorophenyl)-7-[({4-[(3,5-dimethylisoxazol-4- yl)carbonyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin- 4-amine 360 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-{[3-(methylox- y)phenyl]acetyl}morpholin-2-yl)methyl]oxy}quinazolin-4-amine 361 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2- methylpentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 362 7-[({4-[(4-butylphenyl)carbonyl]morpholin-2-yl}methyl)oxy]-N- (3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 363 7-[({4-[(4-chlorophenyl)acetyl]morpholin-2-yl}methyl)oxy]-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 364 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2-propyl- pentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 365 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(4-methyl- pentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 366 N-(3,4-dichlorophenyl)-7-[({4-[(2,5-difluorophenyl)carbonyl] morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 367 7-({[4-(cyclopentylcarbonyl)morpholin-2-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 368 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2-phenyl- butanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 369 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(2,3,6-trifluoro- phenyl)carbonyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine 370 N-(3,4-dichlorophenyl)-7-({[4-(furan-3-ylcarbonyl)morpholin-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 371 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propanoylmorpholin- 2-yl)methyl]oxy}quinazolin-4-amine 372 N-(3,4-dichlorophenyl)-7-{[(4-hexanoylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 373 N-(3,4-dichlorophenyl)-7-({[4-(2-ethylhexanoyl)morpholin-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 374 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(3-phenyl- propanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 375 N-(3,4-dichlorophenyl)-7-({[4-(2,2-dimethylpropanoyl)morpholin- 2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 376 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(naphthalen-1- ylcarbonyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 377 7-[({4-[(2-chloropyridin-3-yl)carbonyl]morpholin-2-yl}meth- yl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 378 7-[({4-[(6-chloropyridin-3-yl)carbonyl]morpholin-2-yl}meth- yl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 379 7-({[4-(1,3-benzodioxol-5-ylcarbonyl)morpholin-2-yl]methyl}oxy)- N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 380 N-(3,4-dichlorophenyl)-6-[(1-methylethyl)oxy]-7-[(morpholin-2- ylmethyl)oxy]quinazolin-4-amine 381 N-(3,4-dichlorophenyl)-6-{[2-(methyloxy)ethyl]oxy}-7- [(morpholin-2-ylmethyl)oxy]quinazolin-4-amine 382 N-(3,4-dichlorophenyl)-6-(ethyloxy)-7-[(morpholin-2- ylmethyl)oxy]quinazolin-4-amine 383 N-(3,4-dichlorophenyl)-6-(ethyloxy)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}quinazolin-4-amine 384 N-(4-bromo-2-methylphenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 385 N-(4-chloro-3-methylphenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 386 N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-N-methylmorpholine-4- carboximidamide 387 N-(4-bromo-3-chlorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 388 N-(3,4-dichlorophenyl)-6-[(1-methylethyl)oxy]-7-{[(4- methylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 389 N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}- 6-{[2-(methyloxy)ethyl]oxy}quinazolin-4-amine 390 N-(4-bromo-2-chlorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 391 7-{[(4-acetyl-1,4-oxazepan-2-yl)methyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 392 4-[(3,4-dichlorophenyl)amino]-7-{[(4-methylmorpholin-2- yl)methyl]oxy}quinazolin-6-ol 393 N-(3-bromo-4-chlorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 394 3-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin-4-yl]-3-oxopropanoic acid 395 methyl 4-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyl- oxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]-4-oxobutanoate 396 N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-3-yl)methyl]oxy}- 6-(methyloxy)quinazolin-4-amine 397 N-(3-bromo-2-chlorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 398 N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyl- oxy)quinazolin-7-yl]oxy}methyl)-N-[2- (methyloxy)ethyl]morpholine-4-carboximidamide 399 N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-N-ethylmorpholine-4- carboximidamide 400 [(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methylox- y)quinazolin-7-yl]oxy}methyl)morpholin-4-yl](piperidin-1- yl)methylidene]cyanamide 401 [(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4- yl](pyrrolidin-1-yl)methylidene]cyanamide 402 [(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl](4- methylpiperazin-1-yl)methylidene]cyanamide 403 N-(3,4-dichlorophenyl)-7-{[(6-ethyl-4,6-dimethylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 404 N-(4-bromo-3-methylphenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 405 N-(3,4-dichlorophenyl)-7-{[(6,6-dimethylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 406 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4,6,6- trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 407 N-(3,4-dichlorophenyl)-7-{[2-(5,5-dimethylmorpholin-2- yl)ethyl]oxy}-6-(methyloxy)quinazolin-4-amine 408 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(4,5,5- trimethylmorpholin-2-yl)ethyl]oxy}quinazolin-4-amine 409 1,1-dimethylethyl 2-(2-{[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}ethyl)-5,5-dimethylmorpholine-4- carboxylate 410 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4,5,5- trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 411 N-(4-bromo-2,3-dichlorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 412 N-(4,5-dichloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 413 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(4,6,6- trimethylmorpholin-2-yl)ethyl]oxy}quinazolin-4-amine 414 N-(4-bromo-2,3-difluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 415 N-(4-bromo-2,5-difluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 416 N-(4-bromo-3,5-difluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 417 N-(3,4-dichloro-2-methylphenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 418 N-(3,4-dichlorophenyl)-7-({[(2R,5S,6S)-5,6-dimethylmorpholin-2- yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 419 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[(2R,5S,6S)-4,5,6- trimethylmorpholin-2-yl]methyl}oxy)quinazolin-4-amine 420 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[(2S,5S,6S)-4,5,6- trimethylmorpholin-2-yl]methyl}oxy)quinazolin-4-amine 421 N-(4-bromo-3-chloro-2-methylphenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 422 N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 423 N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 424 N-(3,4-dichloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 425 N-(3-chloro-2,4-difluorophenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 426 N-(2,3-dichloro-4-methylphenyl)-7-{[(4-methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 427 6-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)-3,3,4-trimethylmorpholin-2-one 428 N-(4-bromo-2,3-dichlorophenyl)-6-(methyloxy)-7-{[(4,5,5- trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 429 N-(4-bromo-5-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5- trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 430 N-(4,5-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5- trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 431 N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5- trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 432 N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5- trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 433 N-(3-chloro-2,4-difluorophenyl)-6-(methyloxy)-7-{[(4,5,5- trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 434 (6S)-6-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-4-methylpiperazin-2-one 435 (6S)-6-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-4-methylpiperazin-2-one 436 (6S)-6-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyl- oxy)quinazolin-7-yl]oxy}methyl)-1,4-dimethylpiperazin-2-one 437 (6S)-6-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyl- oxy)quinazolin-7-yl]oxy}methyl)-1,4-dimethylpiperazin-2-one 438 N-(4-bromo-3-chlorophenyl)-7-{[(3a′S,4R,6′S,6a′R)-2,2- dimethyltetrahydrospiro[1,3-dioxolane-4,3′-furo[3,2-b]furan]-6′- yl]oxy}-6-(methyloxy)quinazolin-4-amine 439 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-5-C-[(methyloxy)methyl]- L-glucitol 440 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-(methylsulfonyl)-L-glucitol 441 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-L-glucitol 442 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-S-methyl-5-thio-D-iditol 443 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-morpholin-4-yl-D-iditol 444 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-(4-methylpiperazin-1-yl)- D-iditol 445 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-pyrrolidin-1-yl-D-iditol 446 2-O-acetyl-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-D-iditol 447 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-D-iditol 448 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-(methylsulfonyl)-D-iditol 449 2-amino-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro- phenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-D-iditol 450 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-(dimethylamino)-D-iditol 451 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-(diethylamino)-D-iditol 452 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-piperidin-1-yl-D-iditol 453 2-(acetylamino)-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro- phenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-D-iditol 454 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-5-C-(trifluoromethyl)-L- glucitol 455 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-[(methylsulfonyl)amino]- D-iditol 456 N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-[(1- methylpyrrolidin-3-yl)oxy]quinazolin-4-amine 457 N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-[(3R)- tetrahydrofuran-3-yloxy]quinazolin-4-amine 458 N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-{[(3S,4R)-4- (methyloxy)tetrahydrofuran-3-yl]oxy}quinazolin-4-amine 459 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-(6-(methyloxy)-4-{[4-(4- methylpiperazin-1-yl)phenyl]amino}quinazolin-7-yl)-D-iditol 460 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[3-fluoro-4-(4- methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7- yl]-D-iditol 461 1,4:3,6-dianhydro-2-deoxy-5-O-[4-{[2,3-dichloro-4-(4- methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7- yl]-2-fluoro-D-iditol 462 1,4:3,6-dianhydro-2-deoxy-5-O-[4-{[3,4-dichloro-2-(4- methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7- yl]-2-fluoro-D-iditol 463 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-C-(trifluoromethyl)-D-glucitol 464 (3,4-dichlorophenyl)[6-(methyloxy)-7-({[4-(tetrahydrofuran-2- ylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)quinazolin-4-amine 465 N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,6aS)-2-(1- methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 466 N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,6aS)-2-(1- methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 467 7-({[(3aR,6aS)-2-acetyloctahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)-N-(4-bromo-3-chloro-2-fluorophenyl)-6- (methyloxy)quinazolin-4-amine 468 N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7- {[(3aR,6aS)-octahydrocyclopenta[c]pyrrol-5- ylmethyl]oxy}quinazolin-4-amine 469 ethyl (3aR,5r,6aS)-5-[({4-[(4-bromo-3-chloro-2-fluorophen- yl)amino]-6-(methyloxy)quinazolin-7-yl}oxy)methyl]hexa- hydrocyclopenta[c]pyrrole-2(1H)-carboxylate 470 N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7- ({[(3aR,6aS)-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)quinazolin-4-amine 471 N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,6aS)-2-ethyloctahydro- cyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine 472 N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,6aS)-2- (2-methylpropyl)octahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)quinazolin-4-amine 473 N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,6aS)-2-methylocta- hydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 474 N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 475 N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 476 N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 477 N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 478 N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,5r,6aS)-2- methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 479 N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 480 N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 481 N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 482 N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 483 N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 484 N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,5r,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 485 N-(3,4-dichlorophenyl)-7-({[(3aR,6aS)-2-methyloctahydro- cyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine 486 N-(3,4-dichlorophenyl)-7-({[(3aR,5r,6aS)-2- methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 487 N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,6aS)-2- ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine 488 N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7- ({[(3aR,6aS)-2-(2-methylpropyl)octahydrocyclopenta[c]pyrrol-5- yl]methyl}oxy)quinazolin-4-amine 489 N-(3,4-dichlorophenyl)-7-[(2-{[(3-endo)-8-methyl-8- azabicyclo[3.2.1]oct-3-yl]amino}ethyl)oxy]-6- (methyloxy)quinazolin-4-amine 490 N-(3,4-dichlorophenyl)-7-({2-[(3-endo)-8-methyl-8- azabicyclo[3.2.1]oct-3-yl]ethyl}oxy)-6-(methyloxy)quinazolin-4- amine 491 N-(3,4-dichlorophenyl)-7-({[(3-endo)-8-methyl-8-azabi- cyclo[3.2.1]oct-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 492 N-(3,4-dichlorophenyl)-7-{[(3-exo)-8-methyl-8- azabicyclo[3.2.1]oct-3-yl]oxy}-6-(methyloxy)quinazolin-4-amine 493 1,1-dimethylethyl (3aR,6aS)-5-({[4-[(4-bromo-3-chloro-2- fluorophenyl)amino]-6-(methyl-oxy)quinazolin-7- yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 494 1,1-dimethylethyl (3aR,6aS)-5-({[4-[(3,4-dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl) hexahydrocyclopenta-[c]pyrrole-2(1H)-carboxylate 495 N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[[(3aR,5r,6aS)- octahydrocyclopenta[c]pyrrol-5-yl]methyl]oxy}quinazolin-4-amine 496 7-{[(3-endo)-8-azabicyclo[3.2.1]oct-3-ylmethyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 497 1,1-dimethylethyl (3-endo)-3-(2-{[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}ethyl)-8-azabicyclo[3.2.1]octane- 8-carboxylate and 498 7-({2-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]ethyl}oxy)-N-(3,4- dichlorophenyl)-6-(methyloxy) quinazolin-4-amine and 499 1,4:3,6-Dianhydro-5-O-[4-[(3,4-dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-O-methyl-D-glucitol 500 3,6-Anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyl- oxy)quinazolin-7-yl]-1,2-O-(1-methylethylidene)-□-D-idofuranose 501 1,4:3,6-dianhydro-5-O-{4-[(3-chloro-2-fluorophenyl)amino]-6- (methyloxy)quin-azolin-7-yl}-2-deoxy-2-fluoro-L-iditol 502 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-(methylsulfonyl)-D-glucitol 503 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-D-glucitol 504 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-S-methyl-5-thio-L-iditol 505 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-morpholin-4-yl-L-iditol 506 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-(4-methylpiperazin-1-yl)-L- iditol 507 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-pyrrolidin-1-yl-L-iditol 508 2-O-acetyl-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-L-iditol 509 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-L-iditol 510 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-(methylsulfonyl)-L-iditol 511 2-amino-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro- phenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-L-iditol 512 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-(dimethylamino)-L-iditol 513 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-(diethylamino)-L-iditol 514 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-piperidin-1-yl-L-iditol 515 2-(acetylamino)-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro- phenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-L-iditol 516 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-5-C-(trifluoromethyl)-D- glucitol 517 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-[(methylsulfonyl)amino]-L- iditol 518 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-(6-(methyloxy)-4-{[4-(4- methylpiperazin-1-yl)phenyl]amino}quinazolin-7-yl)-L-iditol 519 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[3-fluoro-4-(4- methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7- yl]-L-iditol 520 1,4:3,6-dianhydro-2-deoxy-5-O-[4-{[2,3-dichloro-4-(4-methylpiper- azin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-L- iditol and 521 1,4:3,6-dianhydro-2-deoxy-5-O-[4-{[3,4-dichloro-2-(4- methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7- yl]-2-fluoro-L-iditol and a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, solvate, or hydrate thereof.

TABLE 5a Representative IGF-1R Inhibitors Entry Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

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a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, solvate, or hydrate thereof.

TABLE 5b Additional Representative IGF1R Inhibitors Entry Structure Name 1

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N⁶-[3-(diethylamino)propyl]- N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4,6- triamine 2

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N⁶-[2-(diethylamino)ethyl]- N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4,6- triamine 3

N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}-N⁴-[5-(1-methylethyl)- 1H-pyrazol-3-yl]-6-[(3S)-3- methylpiperazin-1-yl]pyrimidine- 2,4-diamine 4

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N²- {[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine 5

N⁴-[3-(1-methylethyl)-1H- pyrazol-5-yl]-6-[(1- methylpyrrolidin-3-yl)oxy]-N²- [(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 6

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-}[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(1- methylpyrrolidin-3- yl)oxy]pyrimidine-2,4-diamine 7

N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}-N⁴-[3-(1-methylethyl)- 1H-pyrazol-5-yl]-6-[(1- methylpyrrolidin-3- yl)oxy]pyrimidine-2,4-diamine 8

N⁴-[2-(diethylamino)ethyl]-N²- {[3-(1-methylethyl)isoxazol-5- yl]methyl}-N⁶-[5-(1-methylethyl)- 1H-pyrazol-3-yl]pyrimidine-2,4,6- triamine 9

N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}-N⁶-[5-(1-methylethyl)- 1H-pyrazol-3-yl]pyrimidine-2,4- diamine 10

N⁴-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(1- methylpiperidin-3-yl)oxy]-N²-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 11

N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}-N⁴-[5-(1-methylethyl)- 1H-pyrazol-5-yl]-6-[(1- methylpiperidin-3- yl)oxy]pyrimidine-2,4-diamine 12

N-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-2-{[(3- phenylisoxazol-5- yl)methyl]oxy}pyrimidin-4-amine 13

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N²-[(4-phenyl-1H- imidazol-2-yl)methyl]pyrimidine- 2,4-diamine 14

6-{[2-(dimethylamino)ethyl]oxy}- N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}-N⁴-[5-(1-methylethyl)- 1H-pyrazol-3-yl]pyrimidine-2,4- diamine 15

N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}-N⁴-[5-(1-methylethyl)- 1H-pyrazol-3-yl]-6-[(2- morpholin-4- ylethyl)oxy]pyrimidine-2,4- diamine 16

N⁴-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(2-morpholin-4- ylethyl)oxy]-N²-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 17

N⁴-[3-(1-methylethyl)-1H- pyrazol-5-yl]-N²-[(3- phenylisoxazol-5-yl)methyl]-6- [(2-piperidin-1- ylethyl)oxy]pyrimidine-2,4- diamine 18

N⁴-[3-(diethylamino)propyl]-N²- {[3-(1-methylethyl)isoxazol-5- yl]methyl}-N⁴-[5-(1-methylethyl)- 1H-pyrazol-3-yl]pyrimidine-2,4,6- triamine 19

N⁴-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(3S)-3- methylpiperazin-1-yl]-N²-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 20

N⁴-[2-(diethylamino)ethyl]-N⁶[5- (1-methylethyl)-1H-pyrazol-3-yl]- N²-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4,6- triamine 21

N⁴-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(1- methylpiperidin-4-yl)oxy]-N²-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 22

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(2-morpholin-4- ylethyl)oxy]pyrimidine-2,4- diamine 23

N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}-N⁴-[3-(1-methylethyl)- 1H-pyrazol-5-yl]-6-[(2-piperidin- 1-ylethyl)oxy]pyrimidine-2,4- diamine 24

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-[3-(diethylamino)propyl]- N²-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 25

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(2-piperidin-1- ylethyl)oxy]pyrimidine-2,4- diamine 26

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(1-methylpiperidin- 3-yl)oxy]pyrimidine-2,4-diamine 27

N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}-N⁴-[3-(1-methylethyl)- 1H-pyrazol-5-yl]-6-[(1- methylpiperidin-4- yl)oxy]pyrimidine-2,4-diamine 28

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-methyl-N²-[(3- methylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 29

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-[(3-methylisoxazol-5- yl)methyl]-6-morpholin-4- ylpyrimidine-2,4-diamine 30

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-[(3-methylisoxazol-5- yl)methyl]-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine 31

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(1-methylpiperidin- 4-yl)oxy]pyrimidine-2,4-diamine 32

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-{[3-(4- fluorophenyl)isoxazol-5- yI]methyI}-6-morpholin-4- ylpyrimidine-2,4-diamine 33

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-{[3-(4- fluorophenyl)isoxazol-5- yl]methyl}-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine 34

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-{[3-(4- fluorophenyl)isoxazol-5- yl]methyl}-6-[(2-morpholin-4- ylethyl)oxy]pyrimidine-2,4- diamine 35

N²-{[3-(4-fluorophenyl)isoxazol- 5-yl]methyl}-N⁴-[3-(1- methylethyl)-1H-pyrazol-5-yl]-6- morpholin-4-ylpyrimidine-2,4- diamine 36

N²-{[3-(4-fluorophenyl)isoxazol- 5-yl]methyl}-N⁴-[3-(1- methylethyl)-1H-pyrazol-5-yl]-6- (4-methylpiperazin-1- yl)pyrimidine-2,4-diamine 37

N²-{[3-(4-fluorophenyl)isoxazol- 5-yl]methyl}-N⁴-[3-(1- methylethyl)-1H-pyrazol-5-yl]-6- [(2-morpholin-4- ylethyl)oxy]pyrimidine-2,4- diamine 38

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N²-[(3-pyridin-3- ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 39

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)-N²- [(3-pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 40

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-morpholin-4-yl-N²-[(3- pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 41

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²5{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-piperazin-1- ylpyrimidine-2,4-diamine 42

6-(4-acetylpiperazin-1-yl)-N⁴(5- cyclopropyl-1H-pyrazol-3-yl)-N²- {[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine 43

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[4- (methylsulfonyl)piperazin-1- yl]pyrimidine-2,4-diamine 44

4-{6-[(5-cyclopropyl-1H-pyrazol- 3-yl)amino]-2-({[3-(1- methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4- yl}piperazine-1-carbaldehyde 45

N⁴-(3-methyl-1H-pyrazol-5-yl)-6- morpholin-4-yl-N²-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 46

6-(4-methylpiperazin-1-yl)-N⁴-(3- methyl-1H-pyrazol-5-yl)-N²-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 47

N⁴-(3-methyl-1H-pyrazol-5-yl)-6- [(2-morpholin-4-ylethyl)oxy]-N²- [(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 48

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N²-[(3-pyridin-4- ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 49

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(3,4- difluorophenyl)isoxazol-5- yl]methyl}-6-methylpyrimidine- 2,4-diamine 50

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(2,4- difluorophenyl)isoxazol-5- yl]methyl}-6-methylpyrimidine- 2,4-diamine 51

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N²-[(3-pyrazin-2- ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 52

5-chloro-N⁴-(3-cyclopropyl-1H- pyrazol-5-yl)-6-morpholin-4-yl- N²-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 53

5-chloro-N⁴-(3-cyclopropyl-1H- pyrazol-5-yl)-6-(4- methylpiperazin-1-yl)-N²-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 54

N²-[(3-methylisoxazol-5- yl)methyl]-6-(4-methylpiperazin- 1-yl)-N⁴-(3-methyl-1H-pyrazol-5- yl)pyrimidine-2,4-diamine 55

N²-[(3-methylisoxazol-5- yl)methyl]-N⁴-(3-methyl-1H- pyrazol-5-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine 56

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)-N²- [(3-pyrimidin-4-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 57

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-[(3-furan-3-ylisoxazol-5- yl)methyl]-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine 58

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N⁶-(8-methyl-8- azabicyclo[3.2.1]oct-3-yl)-N²-[(3- methylisoxazol-5- yl)methyl]pyrimidine-2,4,6- triamine 59

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(5-methyl-2,5- diazabicyclo[2.2.1]hept-2-yl)-N²- [(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 60

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(5-methyl-2,5- diazabicyclo[2.2.1]hept-2-yl)-N²- {[(3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine 61

N⁴-bicyclo[2.2.1]hept-2-yl-N⁶-(5- cyclopropyl-1H-pyrazol-3-yl)-N²- {[3-(1-methytethyl)isoxazol-5- yl]methyl}pyrimidine-2,4,6- triamine 62

N⁴-bicyclo[2.2.1]hept-2-yl-N⁶-(5- cyclopropyl-1H-pyrazol-3-yl)-N²- [3-methytisoxazol-5- yl)methyl]pyrimidine-2,4,6- triamine 63

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-[(3-methylisoxazol-5- yl)methyl]-6-[(1R,4R)-5- (phenylmethyl)-2,5- diazabicyclo[2.2.1]hept-2- yl]pyrimidine-2,4-diamine 64

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(1R,4R)-5- (phenylmethyl)-2,5- diazabicyclo[2.2.1]hept-2- yl]pyrimidine-2,4-diamine 65

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-morpholin-4-yl-N²-[(3- pyrimidin-4-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 66

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N²- [(3-pyrimidin-4-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 67

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(5-fluoropyridin-2- yl)isoxazol-5-yl]methyl}-6- methylpyrimidine-2,4-diamine 68

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)-N²- {[3-(2-thienyl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine 69

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N²- [(3-pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 70

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-(4-methylpiperazin-1-yl)-N²- [(3-pyrimidin-5-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 71

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-morpholin-4-yl)-N²-[(3- pyrimidin-5-ylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 72

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (diethylamino)ethyl]oxy}-N²-{[3- (1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine 73

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine 74

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (diethylamino)ethyl]oxy}-N²-{[3- methylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 75

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-[(3-methylisoxazol-5- yl)methyl]-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine 76

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)-N²- {[3-(1,3-thiazol-2-yl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine 77

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-[2-(dimethylamino)ethoxy]- N²-[(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 78

6-{[2-(dimethylamino)ethyl]oxy}- N²-[(3-methylisoxazol-5- yl)methyl]-N⁴-(3-methyl-1H- pyrazol-5-yl)pyrimidine-2,4- diamine 79

6-{[2-(diethylamino)ethyl]oxy}- N²-[(3-methylisoxazol-5- yl)methyl]-N⁴-(3-methyl-1H- pyrazol-5-yl)pyrimidine-2,4- diamine 80

N²-[(3-methylisoxazol-5- yl)methyl]-N⁴-(3-methyl-1H- pyrazol-5-yl)-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine 81

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-methyl-N²-[2-(3- phenylisoxazol-5- yl)ethyl]pyrimidine-2,4-diamine 82

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-methyl-N²-[1-(3- phenylisoxazol-5- yl)ethyl]pyrimidine-2,4-diamine 83

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-[(3-ethylisoxazol-5- yl)methyl]-6-(4-methytpiperazin- 1-yl)pyrimidine-2,4-diamine 84

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-[(3-ethylisoxazol-5- yl)methyl]-6-morpholin-4- ylpyrimidine-2,4-diamine 85

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N²- [(3-ethylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 86

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-{[2- (diethylamino)ethyl]oxy}-N²- [(3-ethylisoxazol-5- yl)methyl]pyrimidine-2,4-diamine 87

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-[(3-ethylisoxazol-5- yl)methyl]-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine 88

N²-{[3-(2-aminopyrimidin-4- yl)isoxazol-5-yl]methyl}-N⁴-(3- cyclopropyl-1H-pyrazol-5-yl)-6- (4-methylpiperazin-1- yl)pyrimidine-2,4-diamine 89

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-(4-ethylpiperazin-1-yl)-N²- {[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4-diamine 90

2-(1-{6-[(3-cyclopropyl-1H- pyrazol-5-yl)amino]-2-({[3-(1- methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4- yl}piperidin-4-yl)ethanol 91

2-(4-{6-[(3-cyclopropyl-1H- pyrazol-5-yl)amino]-2-({[3-(1- methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4- yl}piperazin-1-yl)ethanol a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, solvate, or hydrate thereof.

TABLE 6 Representative Raf Inhibitors Entry Name 1 6-(2-butyl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4- benzoxazin-3(4H)-one 2 6-[1-hydroxy-3-oxo-2-(2-phenylethyl)-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 3 6-(1-hydroxy-2-{[4-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro- 1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 4 6-(1-hydroxy-2-{[3-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro- 1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 5 6-{2-[(4-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 6 6-(1-hydroxy-3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)-2H- 1,4-benzoxazin-3(4H)-one 7 6-{2-[(3-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 8 6-{2-[(4-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 9 6-[1-hydroxy-3-oxo-2-(3-phenylpropyl)-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 10 6-{2-[(3,4-dichlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 11 6-{1-hydroxy-2-[(4-methylphenyl)methyl]-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 12 6-{2-[(4-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 13 6-[1-hydroxy-2-(1-methylethyl)-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 14 methyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 15 6-{2-[(3,4-dimethylphenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 16 6-(2-{[4-chloro-3-(trifluoromethyl)phenyl]methyl}-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 17 6-(2-{[4-(dimethylamino)phenyl]methyl}-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 18 6-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 19 6-[2-(4-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 20 6-[2-(3,4-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 21 6-[1-hydroxy-2-(4-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 22 3-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-3- (methyloxy)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 23 3-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-2- (1-methylethyl)-3-(methyloxy)-2,3-dihydro-1H-isoindol-1-one 24 3-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-3- hydroxy-2-phenyl-2,3-dihydro-1H-isoindol-1-one 25 3-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-3- hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 26 methyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1-methyl-1H-benzimidazol-2-yl}carbamate 27 3-(1H-benzimidazol-5-yl)-3-hydroxy-2-(phenylmethyl)-2,3- dihydro-1H-isoindol-1-one 28 5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1- yl]-N-methyl-1H-benzimidazole-2-carboxamide 29 3-hydroxy-3-(2-methyl-1H-benzimidazol-5-yl)-2-(phenylmethyl)- 2,3-dihydro-1H-isoindol-1-one 30 7-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1- yl]-3,4-dihydroquinoxalin-2(1H)-one 31 7-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-3,4-dihydroquinoxalin-2(1H)-one 32 1,1-dimethylethyl 4-{[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-6-yl)-1,3-dihydro-2H-isoindol-2- yl]methyl}piperidine-1-carboxylate 33 6-(1-hydroxy-2-{[2-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro- 1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 34 6-{2-[(3-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 35 6-{2-[(2-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 36 6-{2-[(3-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 37 6-{2-[(2-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 38 6-{2-[(2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 39 6-[2-(3-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 40 6-[1-hydroxy-2-(3-iodophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 41 6-[2-(3-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 42 6-[1-hydroxy-2-(3-nitrophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 43 6-{1-hydroxy-2-[3-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 44 6-[1-hydroxy-2-(3-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 45 3-hydroxy-3-(1H-indol-5-yl)-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-one 46 methyl [6-(1-hydroxy-3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1- yl)-1H-benzimidazol-2-yl]carbamate 47 6-[2-(2-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 48 6-{[2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-2H-1,4- benzoxazin-3(4H)-one 49 6-{[2-(1H-benzimidazol-2-yl)phenyl]carbonyl}-2H-1,4-benzoxazin- 3(4H)-one 50 6-(1-hydroxy-3-oxo-2-{[2-(trifluoromethyl)phenyl]methyl}-2,3- dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 51 6-{2-[(5-bromo-2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 52 6-{1-hydroxy-2-[(3-nitrophenyl)methyl]-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 53 6-(1-hydroxy-3-oxo-2-{[3-(trifluoromethyl)phenyl]methyl}-2,3- dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 54 6-(2-{[2,3-bis(methyloxy)phenyl]methyl}-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 55 6-{1-hydroxy-2-[(3-iodophenyl)methyl]-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 56 6-[1-hydroxy-3-oxo-2-({3-[(trifluoromethyl)oxy]phenyl}methyl)- 2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 57 6-(1-hydroxy-2-{[2-(methylthio)phenyl]methyl}-3-oxo-2,3- dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 58 6-[2-(3,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 59 6-{1-hydroxy-2-[3-(1-methylethyl)phenyl]-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 60 6-(1-hydroxy-3-oxo-2-{3-[(trifluoromethyl)oxy]phenyl}-2,3- dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 61 6-{1-hydroxy-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 62 3-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6- yl)-1,3-dihydro-2H-isoindol-2-yl]benzenesulfonamide 63 6-{2-[5-chloro-2-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 64 6-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 65 3-hydroxy-3-(1H-indol-6-yl)-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-one 66 6-[2-(3-fluoro-5-iodophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 67 6-[2-(3-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 68 6-[2-(3,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 69 6-{1-hydroxy-2-[3-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 70 ethyl 3-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin- 6-yl)-1,3-dihydro-2H-isoindol-2-yl]benzoate 71 3-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6- yl)-1,3-dihydro-2H-isoindol-2-yl]benzonitrile 72 6-[2-(2-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 73 6-[2-(3-amino-5-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 74 6-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 75 6-[2-(3-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 76 6-[2-(3-ethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 77 6-[2-(3-ethynylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1-yl]-2H-1,4-benzoxazin-3(4H)-one 78 6-[1-hydroxy-2-(3-hydroxyphenyl)-3-oxo-2,3-dihydro-1H-isoindol- 1-yl]-2H-1,4-benzoxazin-3(4H)-one 79 6-{1-hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 80 6-(1-hydroxy-3-oxo-2-{3-[(phenylmethyl)oxy]phenyl}-2,3-dihydro- 1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 81 3-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6- yyl)-1,3-dihydro-2H-isoindol-2-l]benzamide 82 6-{1-hydroxy-2-[3-(hydroxymethyl)phenyl]-3-oxo-2,3-dihydro-1H- isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 83 6-[2-(2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 84 3-hydroxy-3-[2-(methylamino)-1H-benzimidazol-5-yl]-2- (phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 85 6-(2-biphenyl-3-yl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)- 2H-1,4-benzoxazin-3(4H)-one 86 6-(2-{3-[(dimethylamino)methyl]phenyl}-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 87 6-[2-(3,5-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 88 6-(1-hydroxy-3-oxo-2-piperidin-4-yl-2,3-dihydro-1H-isoindol-1-yl)- 2H-1,4-benzoxazin-3(4H)-one 89 6-[2-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 90 6-[1-hydroxy-2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-2H-1,4-benzoxazin-3(4H)-one 91 N-methyl-2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6- yl)carbonyl]-N-phenylbenzamide 92 methyl {5-[1-(ethyloxy)-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 93 Phenylmethyl 2-[(2-{[(methyloxy)carbonyl]amino}-1H- benzimidazol-5-yl)carbonyl]benzoate 94 3-hydroxy-3-(1H-indazol-5-yl)-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-one 95 3-hydroxy-3-(1H-indazol-6-yl)-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-one 96 ethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 97 2-methylpropyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 98 methyl {5-[1-hydroxy-3-oxo-2-(2-thienylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 99 methyl {5-[1-hydroxy-3-oxo-2-(2-phenylethyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 100 3-[2-amino-1-(1,1-dimethylethyl)-1H-benzimidazol-5-yl]-3- hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 101 3-(2-amino-1H-benzimidazol-5-yl)-3-hydroxy-2-(phenylmethyl)- 2,3-dihydro-1H-isoindol-1-one 102 methyl [5-(1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H- benzimidazol-2-yl]carbamate 103 3-(methyloxy)butyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 104 methyl (5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro- 1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 105 methyl (5-{1-hydroxy-3-oxo-2-[(1S)-1-phenylethyl]-2,3-dihydro- 1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 106 2-(methyloxy)ethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 107 methyl {6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1-methyl-1H-benzimidazol-2-yl}carbamate 108 prop-2-yn-1-yl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 109 but-2-yn-1-yl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 110 1-methylethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 111 methyl {5-[2-(2,3-dihydro-1H-inden-2-yl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 112 methyl {5-[1-hydroxy-3-oxo-2-(pyridin-4-ylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 113 methyl {5-[1-hydroxy-3-oxo-2-(pyridin-3-ylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 114 methyl (6-{2-[(3-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 115 methyl {5-[1-hydroxy-2-(3-methylphenyl)-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 116 methyl [5-(1-hydroxy-2-{[2-(methyloxy)phenyl]methyl}-3-oxo-2,3- dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 117 methyl [5-(1-hydroxy-2-{[3-(methyloxy)phenyl]methyl}-3-oxo-2,3- dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 118 methyl [5-(1-hydroxy-2-{[4-(methyloxy)phenyl]methyl}-3-oxo-2,3- dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 119 methyl (6-{2-[(4-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 120 methyl (6-{2-[(3-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 121 methyl (5-{1-hydroxy-2-[(3-iodophenyl)methyl]-3-oxo-2,3-dihydro- 1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 122 methyl (5-{2-[(3-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 123 methyl (5-{2-[(2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 124 methyl {5-[1-hydroxy-3-oxo-2-(pyridin-2-ylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 125 phenylmethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 126 2-fluoroethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 127 propyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 128 methyl (5-{1-hydroxy-2-[4-(methyloxy)phenyl]-3-oxo-2,3-dihydro- 1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 129 methyl (5-{2-[(2-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 130 methyl (5-{2-[(2-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 131 methyl (5-{1-hydroxy-2-[(3-methylphenyl)methyl]-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 132 methyl (5-{1-hydroxy-2-[(4-methylphenyl)methyl]-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 133 methyl (5-{1-hydroxy-2-[(2-methylphenyl)methyl]-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 134 methyl {5-[2-(3-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 135 methyl {5-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 136 methyl {5-[2-(3-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 137 methyl (5-{1-hydroxy-2-[3-(methyloxy)phenyl]-3-oxo-2,3-dihydro- 1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 138 methyl {5-[2-(4-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 139 methyl {5-[2-(4-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 140 methyl {5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 141 methyl {5-[2-(3,5-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 142 methyl {5-[2-(2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 143 methyl {5-[2-(2-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 144 methyl {5-[1-hydroxy-2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 145 methyl (5-{1-hydroxy-2-[2-(methyloxy)phenyl]-3-oxo-2,3-dihydro- 1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 146 methyl {5-[1-hydroxy-2-(4-methylphenyl)-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 147 methyl (5-{1-hydroxy-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 148 but-2-yn-1-yl (5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 149 N-ethyl-N′-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}urea 150 phenylmethyl (5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 151 methyl {6-[2-(3-amino-5-chlorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 152 piperidin-4-ylmethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 153 methyl {5-[2-(cyclopropylmethyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 154 methyl {5-[2-(2,2-dimethylpropyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 155 methyl {5-[2-(3,5-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 156 methyl {5-[2-(3,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 157 N-ethyl-N′-(5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)urea 158 N′-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}-N,N-dimethylurea 159 methyl {5-[2-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-1-hydroxy- 3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 160 3-(4-methylpiperazin-1-yl)propyl {6-[1-hydroxy-3-oxo-2-(phenyl- methyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 161 methyl {5-[2-(cyclohexylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 162 methyl {5-[1-hydroxy-2-(2-methylpropyl)-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 163 methyl {5-[1-hydroxy-3-oxo-2-(1,3-thiazol-2-ylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 164 methyl {5-[2-(3,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 165 methyl (5-{2-[1-(3,5-difluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 166 methyl (5-{2-[1-(3-fluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 167 methyl [5-(2-cyclohexyl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol- 1-yl)-1H-benzimidazol-2-yl]carbamate 168 methyl {5-[2-(2,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 169 N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}-N′-(phenylmethyl)urea 170 piperidin-4-yl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 171 N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}-N′-methylurea 172 methyl (5-{2-[1-(2-fluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 173 methyl (5-{1-hydroxy-3-oxo-2-[1-(2-thienyl)ethyl]-2,3-dihydro-1H- isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 174 methyl (5-{2-[1-(3-chlorophenyl)ethyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 175 methyl (5-{1-hydroxy-2-[3-methyl-5-(trifluoromethyl)phenyl]-3- oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2- yl)carbamate 176 N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}propanamide 177 methyl {5-[2-(3,4-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 178 methyl {5-[2-(3-ethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 179 methyl {5-[2-(3-ethynylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 180 methyl {5-[2-(4-chloro-3-methylphenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 181 methyl [5-(1-hydroxy-3-oxo-2-{1-[3-(trifluoromethyl)phen- yl]ethyl}-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2- yl]carbamate 182 methyl (5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylpropyl]-2,3-dihydro- 1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 183 methyl [5-(1-hydroxy-3-oxo-2-{2-[(trifluoromethyl)oxy]phenyl}- 2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 184 methyl {5-[2-(2,3-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 185 cyclohexyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 186 tetrahydrofuran-2-ylmethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)- 2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 187 cyclopropylmethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 188 N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}morpholine-4-carboxamide 189 methyl {5-[2-(cyclopentylmethyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 190 methyl {5-[2-(2,3-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 191 methyl {5-[2-(2,3-dihydro-1H-inden-1-yl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 192 methyl (2S)-cyclohexyl[1-hydroxy-1-(2- {[(methyloxy)carbonyl]amino}-1H-benzimidazol-5-yl)- 3-oxo-1,3-dihydro-2H-isoindol-2-yl]ethanoate 193 methyl {5-[2-(2,6-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 194 methyl {5-[2-(3-chloro-4-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 195 but-3-en-1-yl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 196 2,2,2-trifluoroethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 197 methyl {5-[2-(5-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 198 methyl (5-{2-[1-(5-chloro-2-methylphenyl)ethyl]-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 199 methyl (5-{1-hydroxy-3-oxo-2-[(1S)-1-phenylpropyl]-2,3-dihydro- 1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 200 methyl (5-{2-[1-(3-chloro-2-methylphenyl)ethyl]-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 201 methyl (5-{1-hydroxy-2-[1-(5-methyl-2-thienyl)ethyl]-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 202 methyl (5-{2-[1-(5-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 203 methyl {5-[1-hydroxy-2-(3-iodophenyl)-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 204 methyl (5-{1-hydroxy-2-[3-(1-methylethyl)phenyl]-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 205 methyl {5-[2-(furan-2-ylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 206 methyl {5-[1-hydroxy-3-oxo-2-(3-thienylmethyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 207 methyl {5-[2-(cyclobutylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 208 3,3,3-trifluoro-2-hydroxy-N-{5-[1-hydroxy-3-oxo-2- (phenylmethyl)-2,3-dihydro-1H-isoindol-1- yl]-1H-benzimidazol-2-yl}-2-(trifluoromethyl)propanamide 209 methyl (5-{1-hydroxy-2-[1-(4-methyl-2-thienyl)ethyl]-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 210 methyl (5-{2-[1-(4-bromo-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 211 methyl {5-[1-hydroxy-2-(3-{[2-(methyloxy)ethyl]oxy}phenyl)-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 212 tetrahydrofuran-3-ylmethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)- 2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 213 N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}piperidine-1-carboxamide 214 methyl {5-[2-(3-bromo-4-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 215 2,3-dihydroxypropyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 216 methyl {5-[1-hydroxy-3-oxo-2-(tetrahydrofuran-2-ylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 217 methyl (5-{2-[3-(aminocarbonyl)phenyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 218 4,4,4-trifluoro-3-hydroxy-N-{5-[1-hydroxy-3-oxo-2- (phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}-3-(trifluoromethyl)butanamide 219 methyl (5-{1-hydroxy-2-[3-(methylsulfonyl)phenyl]-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 220 methyl (5-{1-hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro- 1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 221 methyl [5-(1-hydroxy-3-oxo-2-{3-[(phenylmethyl)oxy]phenyl}-2,3- dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 222 methyl [5-(2-biphenyl-3-yl-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 223 2,2-dimethyl-3-[(phenylmethyl)oxy]propyl {5-[1-hydroxy-3-oxo-2- (phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 224 methyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 225 methyl {5-[2-(3-cyanophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 226 methyl {5-[2-(3-ethynyl-4-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 227 methyl {5-[2-(4-fluoro-3-methylphenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 228 methyl {6-[2-(3,4-dichloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 229 [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl {5-[1-hydroxy-3-oxo- 2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol- 2-yl}carbamate 230 methyl {5-[2-(5-bromo-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 231 methyl (5-{2-[3-(acetylamino)phenyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 232 methyl (5-{1-hydroxy-3-oxo-2-[3-(phenylmethyl)phenyl]-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 233 methyl (5-{2-[1-(4-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 234 methyl (5-{1-hydroxy-3-oxo-2-[3-(phenylcarbonyl)phenyl]-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 235 methyl [5-(2-{3-[(dimethylamino)methyl]phenyl}-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2- yl]carbamate 236 methyl (5-{2-[3-(aminosulfonyl)phenyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 237 methyl {5-[2-(3-acetylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 238 methyl {5-[2-(3-ethyl-4-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 239 methyl {5-[2-(3-chloro-5-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 240 N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}-2-methylpropanamide 241 methyl (5-{2-[1-(3-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 242 methyl [5-(1-hydroxy-3-oxo-2-pyridin-3-yl-2,3-dihydro-1H- isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 243 methyl (5-{1-hydroxy-3-oxo-2-[3-(phenylamino)phenyl]-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 244 methyl {5-[2-(5-bromo-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 245 methyl {5-[2-(5-chloro-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 246 methyl {5-[2-(3,5-dichloro-4-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 247 2,2-dimethyl-3-(methyloxy)propyl {5-[1-hydroxy-3-oxo-2- (phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 248 3-hydroxy-2,2-dimethylpropyl {5-[1-hydroxy-3-oxo-2- (phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 249 methyl (5-{2-[1-(5-bromo-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 250 methyl {5-[2-(4,5-dichloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 251 methyl {5-[2-(3-bromo-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 252 methyl {5-[2-(3-chloro-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 253 N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}pent-4-ynamide 254 methyl (6-{1-methyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 255 methyl [5-(1-hydroxy-3-oxo-2-{3-[(1,1,2,2- tetrafluoroethyl)oxy]phenyl}-2,3-dihydro-1H-isoindol-1-yl)-1H- benzimidazol-2-yl]carbamate 256 methyl {5-[1-hydroxy-3-oxo-2-(3-piperidin-4-ylphenyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 257 methyl {5-[2-(3-ethenylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 258 methyl (5-{2-[3-(dimethylamino)phenyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 259 2,2-difluoro-N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}cyclopropanecarboxamide 260 N-ethyl-N′-{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}urea 261 methyl {5-[2-(3-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 262 N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}-4-[(phenylmethyl)oxy]butanamide 263 N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}-4-piperidin-1-ylbutanamide 264 N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}-4-(4-methylpiperazin-1-yl)butanamide 265 N-{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}butanamide 266 methyl {6-[2-(3-bromophenyl)-5,6-dichloro-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 267 methyl [5-(1-hydroxy-2-{3-[methyl(phenyl)amino]phenyl}-3-oxo- 2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 268 methyl {5-[1-hydroxy-3-oxo-2-(phenylsulfonyl)-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 269 methyl {5-[(2-{[(phenylamino)carbonyl]amino}phenyl)carbonyl]- 1H-benzimidazol-2-yl}carbamate 270 methyl (5-{[2-({[(phenylmethyl)oxy]carbonyl}amino)phen- yl]carbonyl}-1H-benzimidazol-2-yl)carbamate 271 methyl [5-({2-[(2-phenylhydrazino)carbonyl]phenyl}carbonyl)-1H- benzimidazol-2-yl]carbamate 272 methyl {5-[(2-{[(phenyloxy)amino]carbonyl}phenyl)carbonyl]-1H- benzimidazol-2-yl}carbamate 273 but-2-yn-1-yl {5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 274 N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}-3-piperidin-1-ylpropanamide 275 N-{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}propanamide 276 N-(4-fluorophenyl)-2-{[2-(pent-4-ynoylamino)-1H-benzimidazol-6- yl]carbonyl}benzamide 277 4-(diethylamino)-N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}butanamide 278 N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}-4-pyrrolidin-1-ylbutanamide 279 3-piperidin-1-ylpropyl {6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 280 3-(4-methylpiperazin-1-yl)propyl {6-[2-(4-fluorophenyl)-1- hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 281 methyl {5-[2-(3-bromophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1- yl]-1H-benzimidazol-2-yl}carbamate 282 methyl {5-[2-(3-ethynyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 283 2-piperidin-1-ylethyl {5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 284 methyl {5-[2-(3-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 285 methyl {5-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 286 N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol- 1-yl]-1H-benzimidazol-2-yl}-2,2-dimethyl-3-piperidin-1- ylpropanamide 287 N-{5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}-4-piperidin-1-ylbutanamide 288 N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-4-piperidin-1- ylbutanamide 289 methyl [6-({2-[(phenylcarbonyl)amino]phenyl}carbonyl)-1H- benzimidazol-2-yl]carbamate 290 methyl {5-[1-hydroxy-2-(3-morpholin-4-ylphenyl)-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 291 2-(dimethylamino)ethyl {6-[2-(3-chloro-2-fluorophenyl)-1- hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 292 2-(diethylamino)ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy- 3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 293 2-piperidin-1-ylethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 294 3-piperidin-1-ylpropyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy- 3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 295 2-piperidin-1-ylethyl {6-[2-(3-bromophenyl)-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 296 methyl {6-[2-(3-bromophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 297 2-[methyl(phenylmethyl)amino]ethyl {5-[2-(3-chloro-2- fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl}carbamate 298 methyl {5-[1-hydroxy-3-oxo-2-(3-pyrrolidin-1-ylphenyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 299 methyl {5-[2-(5-chloro-2,3-difluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 300 methyl {5-[1-hydroxy-3-oxo-2-(pyrrolidin-2-ylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 301 methyl {5-[1-hydroxy-3-oxo-2-(pyrrolidin-3-ylmethyl)-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 302 (1-methylpiperidin-2-yl)methyl {6-[2-(3-chloro-2-fluorophenyl)-1- hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 303 [(2S)-1-methylpyrrolidin-2-yl]methyl {6-[2-(3-chloro-2-fluoro- phenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl}carbamate 304 octahydro-2H-quinolizin-1-ylmethyl {6-[2-(3-chloro-2- fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H- benzimidazol-2-yl}carbamate 305 methyl {5-[2-(5-bromo-2-methylphenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 306 5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1,3-dihydro-2H-benzimidazol-2-one 307 methyl {5-[2-(3-bromo-2,5-difluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 308 2-morpholin-4-ylethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy- 3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 309 (1-methylpiperidin-3-yl)methyl {6-[2-(3-chloro-2-fluorophenyl)-1- hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 310 methyl (5-{2-[5-chloro-2-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 311 methyl [5-(2-{3-[cyclohexyl(methyl)amino]phenyl}-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2- yl]carbamate 312 8-azabicyclo[3.2.1]oct-3-ylmethyl {6-[2-(3-chloro-2-fluorophenyl)- 1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol- 2-yl}carbamate 313 methyl {6-[1-(3-bromophenyl)-5-oxopyrrolidin-2-yl]-1H- benzimidazol-2-yl}carbamate 314 (1-methylpiperidin-4-yl)methyl {5-[1-hydroxy-3-oxo-2-(phenyl- methyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 315 1,1-dimethylethyl 4-({[({5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}amino)carbonyl]oxy}methyl)piperidine-1-carboxylate 316 (1-methylpiperidin-4-yl)methyl {5-[2-(3-chloro-2-fluorophenyl)-1- hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 317 2-(1-methylpiperidin-4-yl)ethyl {5-[2-(3-chloro-2-fluorophenyl)-1- hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 318 methyl ({6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}amino)(oxo)acetate 319 N-(5-{1-hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro-1H- isoindol-1-yl}-1H-benzimidazol-2-yl)-4-piperidin-1-ylbutanamide 320 methyl {6-[2-(3-bromophenyl)-1-methyl-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 321 4-(diethylamino)but-2-yn-1-yl {6-[2-(3-chloro-2-fluorophenyl)-1- hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 322 methyl {5-[2-(3-chloro-2,6-difluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 323 2-(2-oxopyrrolidin-1-yl)ethyl {6-[2-(3-chloro-2-fluorophenyl)-1- hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 324 2-(2,5-dioxopyrrolidin-1-yl)ethyl {6-[2-(3-chloro-2-fluorophenyl)- 1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol- 2-yl}carbamate 325 2,2,3,3-tetrafluorocyclobutyl {5-[2-(3-chloro-2-fluorophenyl)-1- hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 326 1-acetyl-N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}piperidine-4- carboxamide 327 N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}cyclobutanecarboxamide 328 methyl [5-(2-{3-[ethyl(phenyl)amino]phenyl}-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 329 N-{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-2,2- difluorocyclopropanecarboxamide 330 cyclobutyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 331 2,2-difluoroethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 332 2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyridin-2-ylamino)- 1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 333 1-methylethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 334 cyclopropylmethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 335 N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}cyclopropanecarboxamide 336 2-(methyloxy)ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 337 tetrahydrofuran-2-ylmethyl {6-[2-(3-chloro-2-fluorophenyl)-1- hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 338 N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-2-(2-thienyl)acetamide 339 methyl {6-[2-(3-chloro-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 340 ethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 341 2-fluoroethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 342 methyl (5-{1-hydroxy-3-oxo-2-[2-(phenyloxy)phenyl]-2,3-dihydro- 1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 343 N′-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-N,N- diethylpentanediamide 344 cyclobutylmethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 345 2,2,2-trifluoroethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 346 methyl (5-{2-[3-(1,1-dimethylethyl)phenyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 347 methyl {6-[2-(3-chloro-2-fluorophenyl)-7-fluoro-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 348 2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(phenylamino)-1H- benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 349 methyl {6-[4,7-dichloro-2-(3-chloro-2-fluorophenyl)-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 350 phenylmethyl 2-[(2-{[(ethyloxy)carbonyl]amino}-1,3-benzoxazol- 5-yl)carbonyl]benzoate 351 methyl {5-[2-(5-chloro-3-ethynyl-2-methylphenyl)-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 352 methyl {5-[2-(5-ethynyl-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 353 methyl {5-[2-(3-ethynyl-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 354 2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyrimidin-2-ylamino)- 1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 355 methyl {5-[2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 356 2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(1,3-thiazol-2- ylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 357 ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1,3-benzoxazol-2-yl}carbamate 358 methyl {5-[2-(5-chloro-3-iodo-2-methylphenyl)-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 359 methyl {5-[2-(3-ethyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 360 methyl {5-[2-(5-ethynyl-2-methylphenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 361 2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyrazin-2-ylamino)- 1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 362 methyl {5-[2-(2-fluoro-3-iodophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 363 methyl {6-[2-(5-ethynyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 364 2-(3-ethynyl-2-fluorophenyl)-3-hydroxy-3-[2-(pyrimidin-2- ylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 365 methyl {5-[2-(2,5-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 366 methyl {5-[2-(3-ethenyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 367 methyl (6-{2-[2-fluoro-3-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 368 methyl (5-{1-hydroxy-2-[2-methyl-5-(methyloxy)phenyl]-3-oxo- 12,3-dihydro-1H-isoindol-1-yl}-H-benzimidazol-2-yl)carbamate 369 methyl {5-[2-(3-ethynyl-2-fluorophenyl)-7-fluoro-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 370 methyl {5-[2-(2-fluoro-3-prop-1-yn-1-ylphenyl)-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 371 methyl {5-[2-(5-chloro-2-methylphenyl)-7-fluoro-1-hydroxy-3-oxo- 2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 372 methyl {5-[2-(3-ethynyl-2-methylphenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 373 3-hydroxy-2-[3-(methyloxy)phenyl]-3-[2-(pyrimidin-2-ylamino)- 1H-benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one 374 3-hydroxy-2-(3-methylphenyl)-3-[2-(pyrimidin-2-ylamino)-1H- benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one 375 2-(5-chloro-2-methylphenyl)-3-hydroxy-3-[2-(pyrimidin-2- ylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one 376 methyl {6-[2-(5-chloro-2-methylphenyl)-4,7-difluoro-1-hydroxy-3- oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2- yl}carbamate 377 methyl {5-[2-(3-ethynyl-2-fluorophenyl)-3-oxo-2,3-dihydro-1H- isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 378 2-(3-chloro-2-fluorophenyl)-3-{2-[(6-chloropyridazin-3-yl)amino]- 1H-benzimidazol-5-yl}-3-hydroxy-2,3-dihydro-1H-isoindol-1-one 379 2-(3-chloro-2-fluorophenyl)-4,7-difluoro-3-hydroxy-3-[2- (pyrimidin-2-ylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H- isoindol-1-one 380 methyl {5-[2-(2-fluoro-5-methylphenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 381 methyl (5-{2-[2-fluoro-5-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 382 methyl (5-{1-hydroxy-2-[5-methyl-2-(methyloxy)phenyl]-3-oxo- 2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 383 methyl {5-[2-(3-ethynyl-5-methylphenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 384 2-(3-chloro-2-fluorophenyl)-3-{2-[(5-chloropyrimidin-2-yl)amino]- 1H-benzimidazol-5-yl}-3-hydroxy-2,3-dihydro-1H-isoindol-1-one 385 2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-{2-[(4-methylpyrimidin- 2-yl)amino]-1H-benzimidazol-5-yl}-2,3-dihydro-1H-isoindol-1-one 386 3-(2-{[4,6-bis(methyloxy)pyrimidin-2-yl]amino}-1H-benzimidazol- 5-yl)-2-(3-chloro-2-fluorophenyl)-3-hydroxy-2,3-dihydro-1H- isoindol-1-one 387 2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-(2-{[4-methyl-6- (methyloxy)pyrimidin-2-yl]amino}-1H-benzimidazol-5-yl)-2,3- dihydro-1H-isoindol-1-one 388 3-hydroxy-2-(3-methylphenyl)-3-[2-(pyrazin-2-ylamino)-1H- benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one 389 2-(5-chloro-2-methylphenyl)-3-hydroxy-3-[2-(pyrazin-2-ylamino)- 1H-benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one 390 methyl {6-[2-(2-fluoro-3-methylphenyl)-1-hydroxy-3-oxo-2,3- dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 391 3-hydroxy-2-[3-(methyloxy)phenyl]-3-[2-(pyrazin-2-ylamino)-1H- benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 392 methyl {6-[(2-{[(2-thienylmethyl)amino]car- bonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 393 methyl {6-[(2-{[(3-methylphenyl)amino]car- bonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 394 methyl {6-[(2-{[(3-bromophenyl)amino]car- bonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 395 methyl {6-[(2-{[(3-chlorophenyl)amino]carbonyl}phenyl)carbonyl]- 1H-benzimidazol-2-yl}carbamate 396 methyl {6-[(2-{[(3-fluorophenyl)amino]carbonyl}phenyl)carbonyl]- 1H-benzimidazol-2-yl}carbamate 397 methyl (6-{[2-({[3-(methyloxy)phenyl]amino}carbonyl)phen- yl]carbonyl}-1H-benzimidazol-2-yl)carbamate 398 methyl (6-{[2-({[3-(trifluoromethyl)phenyl]amino}carbonyl)phen- yl]carbonyl}-1H-benzimidazol-2-yl)carbamate 399 methyl {6-[(2-{[(3-ethylphenyl)amino]carbonyl}phenyl)carbonyl]- 1H-benzimidazol-2-yl}carbamate 400 methyl {6-[(2-{[(3-ethynylphenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 401 methyl {6-[(2-{[(3-chloro-4-fluorophenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 402 methyl {6-[(2-{[(5-chloro-2-fluorophenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 403 methyl {6-[(2-{[(3-iodophenyl)amino]carbonyl}phenyl)carbonyl]- 1H-benzimidazol-2-yl}carbamate 404 methyl (6-{[2-({[3-(1-methylethyl)phenyl]amino}car- bonyl)phenyl]carbonyl}-1H-benzimidazol-2-yl)carbamate 405 methyl {6-[(2-{[(3-thienylmethyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 406 methyl {6-[(2-{[(3-bromo-4-fluorophenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 407 methyl {6-[(2-{[(3-chloro-2-fluorophenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 408 methyl {6-[(2-{[(4-fluoro-3-methylphenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 409 methyl {6-[(2-{[(5-bromo-2-fluorophenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 410 methyl {6-[(2-{[(5-bromo-2,4-difluorophenyl)amino]car- bonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 411 methyl {6-[(2-{[(5-chloro-2,4-difluorophenyl)amino]car- bonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 412 methyl {6-[(2-{[(3-bromo-2-fluorophenyl)amino]car- bonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 413 methyl {6-[(2-{[(3-ethenylphenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 414 methyl {6-[(2-{[(3-ethynyl-2-fluorophenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 415 methyl {6-[(2-{[(5-chloro-2-methylphenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 416 methyl {6-[(2-{[(5-bromo-2-methylphenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 417 methyl {6-[(2-{[(2-fluoro-3-iodophenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 418 methyl {6-[(2-{[(3-ethenyl-2-fluorophenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate 419 methyl {6-[(2-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phen- yl)carbonyl]-1H-benzimidazol-2-yl}carbamate and a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, solvate, or hydrate thereof.

TABLE 7 Representative EGFR and/or VEGFR Inhibitors Entry Name 1 (3Z)-3-[[5-(methyloxy)-1H-benzimidazol-2- yl](phenyl)methylidene]-5-{[1-(phenylmethyl)pyrrolidin-3- yl]amino}-1,3-dihydro-2H-indol-2-one 2 (3Z)-5-[(1-ethylpiperidin-3-yl)amino]-3-[[5-(methyloxy)-1H- benzimidazol-2-yl](phenyl)methylidene]-1,3-dihydro-2H-indol-2- one 3 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[5-(methyloxy)-1H- benzimidazol-2-yl](phenyl)methylidene]-1,3-dihydro-2H-indol-2- one 4 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[1H-imidazol-2- yl(phenyl)methylidene]-1,3-dihydro-2H-indol-2-one 5 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{[5-(methyloxy)-1H- benzimidazol-2-yl][4-(methyloxy)phenyl]methylidene}-1,3- dihydro-2H-indol-2-one 6 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[5-(methyloxy)-1H- benzimidazol-2-yl](4-methylphenyl)methylidene]-1,3-dihydro-2H- indol-2-one 7 (3Z)-3-[1H-benzimidazol-2-yl(4-nitrophenyl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 8 (3Z)-3-{1H-benzimidazol-2-yl[4-(methyloxy)phenyl]methylidene}- 5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 9 (3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 10 (3Z)-3-[[5-(methyloxy)-1H-benzimidazol-2- yl](phenyl)methylidene]-5-[(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,3-dihydro-2H-indol-2-one 11 (3Z)-3-[(4-aminophenyl)(1H-benzimidazol-2-yl)methylidene]-5- [(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 12 (3Z)-3-[1H-benzimidazol-2-yl(4-methylphenyl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 13 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[1H-imidazol-2-yl(4- methylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one 14 (3Z)-5-[(1-ethylpiperidin-4-yl)oxy]-3-[[5-(methyloxy)-1H- benzimidazol-2-yl](phenyl)methylidene]-1,3-dihydro-2H-indol-2- one 15 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{1H-imidazol-2-yl[4- (methyloxy)phenyl]methylidene}-1,3-dihydro-2H-indol-2-one 16 (3Z)-3-[1H-benzimidazol-2-yl(4-fluorophenyl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 17 (3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5- [(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 18 (3Z)-3-[1H-benzimidazol-2-yl(3-fluorophenyl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 19 (3Z)-3-[1H-benzimidazol-2-yl(3-nitrophenyl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 20 3-((Z)-1H-benzimidazol-2-yl{5-[(1-ethylpiperidin-4-yl)amino]-2- oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)benzonitrile 21 (3Z)-3-[(3-aminophenyl)(1H-benzimidazol-2-yl)methylidene]-5- [(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 22 (3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-(piperidin-4- ylamino)-1,3-dihydro-2H-indol-2-one 23 3-((Z)-1H-benzimidazol-2-yl{5-[(1-ethylpiperidin-4-yl)amino]-2- oxo-1,2-dihydro-3H-indol-3- ylidene}methyl)benzenecarboximidamide 24 (3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-({1-[2- (methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 25 (3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-[(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 26 (3Z)-3-{1H-benzimidazol-2-yl[3-(methyloxy)phenyl]methylidene}- 5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 27 (3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 28 2-(2-{2-[(Z)-{5-[(1-ethylpiperidin-4-yl)amino]-2-oxo-1,2-dihydro- 3H-indol-3-ylidene}(phenyl)methyl]-1H-imidazol-4-yl}ethyl)-1H- isoindole-1,3(2H)-dione 29 (3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-({1-[2- (dimethylamino)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol- 2-one 30 (3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-{[1- y(methylsulfonyl)piperidin-4-l]amino}-1,3-dihydro-2H-indol-2-one 31 (3Z)-5-(8-azabicyclo[3.2.1]oct-3-ylamino)-3-[1H-benzimidazol-2- yl(phenyl)methylidene]-1,3-dihydro-2H-indol-2-one 32 (3Z)-3-{1H-benzimidazol-2-yl[3-(methyloxy)phenyl]methylidene}- 5-[(1-ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one 33 (3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5- [(1-ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one 34 (3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-{[1- (phenylmethyl)piperidin-4-yl]oxy}-1,3-dihydro-2H-indol-2-one 35 (3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-[(1- ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one 36 (3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5- ({1-[2-(methyloxy)ethyl]piperidin-4-yl}oxy)-1,3-dihydro-2H-indol- 2-one 37 (3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-({1- [2-(methyloxy)ethyl]piperidin-4-yl}oxy)-1,3-dihydro-2H-indol-2- one 38 (3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-({1- [2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 39 (3Z)-3-{1H-benzimidazol-2-yl[3-(methyloxy)phenyl]methylidene}- 5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H- indol-2-one 40 (3Z)-3-[(3-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2- (methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 41 (3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2- (methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 42 (3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5- ({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H- indol-2-one 43 (3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-[(1- ethylpiperidin-4-yl)(methyl)amino]-1,3-dihydro-2H-indol-2-one 44 (3Z)-3-[(3-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1- ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one 45 (3Z)-3-[1H-benzimidazol-2-yl(4-chlorophenyl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 46 (3Z)-3-[1H-benzimidazol-2-yl(3-fluorophenyl)methylidene]-5-({1- [2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 47 (3Z)-3-[1H-benzimidazol-2-yl(4-fluorophenyl)methylidene]-5-({1- [2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 48 (3Z)-3-[(3-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 49 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(1H- imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 50 (3Z)-3-[1H-benzimidazol-2-yl(3-fluoro-4-methylphenyl)methyl- idene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 51 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(4- ymethyl-1H-imidazol-2-l)methylidene]-1,3-dihydro-2H-indol-2-one 52 (3Z)-3-[1H-benzimidazol-2-yl(4-fluoro-3-methylphenyl)methyl- idene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 53 (3Z)-3-[(3-chloro-4-fluorophenyl)(1H-imidazol-2-yl)methylidene]- 5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 54 (3Z)-3-[(3,4-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1- 1ethylpiperidin-4-yl)amino]-,3-dihydro-2H-indol-2-one 55 (3Z)-3-[(5-chloro-1H-benzimidazol-2-yl)(phenyl)methylidene]-5- [(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 56 (3Z)-3-[(5-chloro-1H-benzimidazol-2-yl)(3,5-difluorophen- yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H- indol-2-one 57 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluoro-4- methylphenyl)(1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H- indol-2-one 58 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(4-fluorophenyl)(1H- imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 59 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[1H-imidazol-2-yl(4- propylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one 60 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{1H-imidazol-2-yl[4- (trifluoromethyl)phenyl]methylidene}-1,3-dihydro-2H-indol-2-one 61 (3E)-3-[(3,5-difluorophenyl)(5-fluoro-1H-benzimidazol-2- yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H- indol-2-one 62 (3Z)-3-[(3,5-difluorophenyl)(5-fluoro-1H-benzimidazol-2- yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H- indol-2-one 63 (3Z)-3-[(3-fluoro-4-methylphenyl)(1H-imidazol-2-yl)methylidene]- 5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H- indol-2-one 64 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(4-methyl-1H-imidazol-2- yl)(4-methylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one 65 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[3-fluoro-4- (trifluoromethyl)phenyl](1H-imidazol-2-yl)methylidene]-1,3- dihydro-2H-indol-2-one 66 (3Z)-3-[(4-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 67 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluoro-4- methylphenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-1,3- dihydro-2H-indol-2-one 68 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{1H-imidazol-2-yl[6- (trifluoromethyl)pyridin-3-yl]methylidene}-1,3-dihydro-2H-indol- 2-one 69 (3Z)-3-[1H-imidazol-2-yl(4-methylphenyl)methylidene]-5-({1-[2- (methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 70 (3Z)-3-[(3-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]- 5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H- indol-2-one 71 (3Z)-3-{1H-imidazol-2-yl[4-(trifluoromethyl)phenyl]methylidene}- 5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H- indol-2-one 72 (3Z)-3-[(5-chloro-1H-benzimidazol-2-yl)(phenyl)methylidene]-5- ({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H- indol-2-one 73 (3Z)-3-[(3,5-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 74 (3Z)-3-[(3,5-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methyl- idene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 75 (3Z)-3-[(3,5-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1- [2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 76 (3Z)-3-[(3,5-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methyl- idene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3- dihydro-2H-indol-2-one 77 (3Z)-3-[(4-methyl-1H-imidazol-2-yl)(4-methylphenyl)methyl- idene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3- dihydro-2H-indol-2-one 78 (3Z)-3-[(4-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2- (methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 79 (3Z)-3-[(3,4-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1- [2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 80 (3Z)-3-[(3-chloro-4-fluorophenyl)(1H-imidazol-2-yl)methylidene]- 5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H- indol-2-one 81 (3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5- (piperidin-4-ylamino)-1,3-dihydro-2H-indol-2-one 82 (3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-(2- piperidin-1-ylethyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2- one 83 (3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-(2- morpholin-4-ylethyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2- one 84 (3Z)-5-({1-[2-(diethylamino)ethyl]piperidin-4-yl}amino)-3-[(3- fluorophenyl)(1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H- indol-2-one 85 (3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-(2- pyrrolidin-1-ylethyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2- one 86 (3Z)-3-[1H-imidazol-2-yl(4-methylphenyl)methylidene]-5-[(1- methylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 87 (3Z)-3-[(3-fluorophenyl)(1H-1,2,4-triazol-5-yl)methylidene]-5-({1- [2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 88 ethyl 2-{(Z)-(3-fluorophenyl)[5-({1-[2-(methyloxy)ethyl]piperidin- 4-yl}amino)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}-4- methyl-1H-imidazole-5-carboxylate 89 (3Z)-3-[1H-imidazol-2-yl(phenyl)methylidene]-5-({1-[2- (methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 90 (3Z)-3-{1H-imidazol-2-yl[4-(methyloxy)phenyl]methylidene}-5- ({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H- indol-2-one 91 (3Z)-3-[(4-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2- (methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 92 (3Z)-3-[[3-fluoro-4-(trifluoromethyl)phenyl](1H-imidazol-2- yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)- 1,3-dihydro-2H-indol-2-one 93 (3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1- (methylsulfonyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one 94 (3Z)-3-[1H-imidazol-2-yl(4-propylphenyl)methylidene]-5-({1-[2- (methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2- one 95 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(4- phenyl-1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 96 (3Z)-3-[(3-fluorophenyl)(4-phenyl-1H-imidazol-2-yl)methylidene]- 5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H- indol-2-one 97 (3Z)-3-[(3-fluoro-4-methylphenyl)(4-methyl-1H-imidazol-2- yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)- 1,3-dihydro-2H-indol-2-one 98 (3Z)-3-{1H-imidazol-2-yl[6-(trifluoromethyl)pyridin-3- yl]methylidene}-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)- 1,3-dihydro-2H-indol-2-one 99 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(1H- 1,2,4-triazol-5-yl)methylidene]-1,3-dihydro-2H-indol-2-one 100 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[2-fluoro-4-(trifluorometh- yl)phenyl](1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2- one 101 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{(4-methyl-1H-imidazol-2- yl)[4-(trifluoromethyl)phenyl]methylidene}-1,3-dihydro-2H-indol- 2-one 102 (3Z)-3-[(4-chlorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]- 5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 103 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[3-fluoro-4- (trifluoromethyl)phenyl](4-methyl-1H-imidazol-2-yl)methylidene]- 1,3-dihydro-2H-indol-2-one 104 (3Z)-3-[(3,4-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methyli- dene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 105 (3Z)-3-[(3-chloro-4-fluorophenyl)(4-methyl-1H-imidazol-2- yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H- indol-2-one 106 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(4-fluorophenyl)(4- methyl-1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 107 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(2-fluorophenyl)(1H- imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 108 (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[2-fluoro-4- (trifluoromethyl)phenyl](4-methyl-1H-imidazol-2-yl)methylidene]- 1,3-dihydro-2H-indol-2-one 109 (3Z)-3-[(2,3-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 110 (3Z)-3-[(2,3-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methyli- dene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 111 (3Z)-3-[(2,4-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methyli- dene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 112 (3Z)-3-[(2,4-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1- ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 113 (3Z)-3-[(2-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]- 5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 114 (3Z)-3-[(3-trifluoromethylphenyl)(1H-imidazol-2-yl)methylidene]- 5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 115 (3Z)-3-[(3-trifluoromethylphenyl)(4-methyl-1H-imidazol-2- yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H- indol-2-one 116 (3Z)-3-[(2,4-dichloro-5-fluorophenyl)(1H-imidazol-2-yl)methyli- dene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 117 (3Z)-3-[(2,4-dichloro-5-fluorophenyl)(4-methyl-1H-imidazol-2- yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H- indol-2-one 118 (3Z)-3-[(4-chloro-2-fluorophenyl)(4-methyl-1H-imidazol-2- yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H- indol-2-one and a single geometric isomer, stereoisomer, racemate, enantiomer, or odiastereomer, thereof and ptionally as a pharmaceutically acceptable salt, solvate, or hydrate thereof.

General Administration

In one aspect, the invention provides pharmaceutical compositions comprising an inhibitor of MEK according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. In certain other embodiments, administration may preferably be by the oral route. Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

The compositions can include a conventional pharmaceutical carrier, excipient, and/or adjuvants and a compound of Formula I, and, in addition, may include other medicinal agents and pharmaceutical agents that are generally administered to a patient being treated for cancer.

Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.

The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptable salts or hydrates, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.

Representative pharmaceutical formulations containing a compound of Formula I are described below in the Pharmaceutical Composition Examples.

Utility

Certain compounds of Formula I have been tested using the assay described Biological Example 1 and have been determined to be MEK inhibitors. As such, compounds of Formula I are useful for treating diseases, particularly cancer in which MEK activity contributes to the pathology and/or symptomatology of the disease. For example, cancer in which MEK activity contributes to its pathology and/or symptomatology include malignant melanomas, colon cancer, rectal cancer, pancreatic cancer, lung cancer, papillary and anaplastic thyroid cancer, and endometrial cancer, ovarian cancer, and the like.

Suitable in vitro assays for measuring MEK activity and the inhibition thereof by compounds are known in the art. For example, see WO 2006/061712 for measuring MEK1 and MEK2 in vitro. For further details of an in vitro assay for measuring MEK activity see Biological Examples, Example 1 infra. Following the examples disclosed herein, as well as those disclosed in the art, a person of ordinary skill in the art can determine the inhibitory activity of a compound of this invention.

Assays for measurement of in vitro efficacy in treatment of cancer are known in the art. For example, see WO 2006/061712, which is herein incorporated by reference, for cell-based assays for colon cancer. In addition, cell-based tumor models are described in Biological Examples, Example 2 and 3 infra.

Suitable in vivo models for cancer are known to those of ordinary skill in the art (including WO 2006/061712). For further details of in vivo models for colorectal cancer, melanoma, breast adenocarcinoma, and lung anaplastic carcinoma, see Biological Examples 4 and 5, infra. Biological Example 5 describes a particular combination of treatments. In conjunction with what is known in the art, one of ordinary skill in the art would know how to follow these examples to test other combinations of treatments.

General Synthesis

Compounds of this invention can be made by the synthetic procedures described below. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4^(th) Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein take place at atmospheric pressure and over a temperature range from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C. and most preferably at about room (or ambient) temperature, e.g., about 20° C. Unless otherwise stated (as in the case of an hydrogenation), all reactions are performed under an atmosphere of nitrogen.

Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure. Compounds of Formula I that may be prepared through the syntheses described herein may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention. Some of the compounds of the invention may exist as tautomers. For example, where a ketone or aldehyde is present, the molecule may exist in the enol form; where an amide is present, the molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention.

The present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula I. For example, when compounds of Formula I contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When compounds of Formula I contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable “protecting group” or “protective group”. A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula I can be prepared by methods well known in the art.

Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.

In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

The chemistry for the preparation of the compounds of this invention is known to those skilled in the art.

An intermediate of Formula II:

where R⁷, X, R¹⁰, R¹², R¹⁴, and R¹⁶ are as defined in the Summary of the Invention for Group A can be prepared using procedures known to one of ordinary skill in the art. In particular, see (for example) U.S. Pat. No. 7,019,033, WO 2002006213, WO 2003062191, WO 2003062189, WO 2002018319, WO2001005392, WO 2000064856, WO 2001005392, WO 9901421, WO 2004056789, Davis, E. M. et al. Org. Process Res. & Dev. 2005, 9, 843-6, and Shapiro, N. et al. Synthetic Commun. 2005, 35, 2265-9 which are incorporated by reference herein. The following intermediates were prepared using similar procedures as described in the above references: 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid; 2-[(2-chloro-4-iodophenyl)amino]-3,4-difluorobenzoic acid; 4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid; 4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid; and 2-[(4-bromo-2-fluorophenyl)amino]-3,4-difluorobenzoic acid.

An intermediate of Formula III(a) or III(b):

where R⁷, X, R¹⁰, R¹², and R¹⁴ are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular for formula III(a), where R¹⁴ is amino or alkyl (particularly methyl); R¹⁰ is halo (particularly fluoro); R⁷ is hydrogen or halo (particularly bromo or chloro); X is halo (particularly chloro); and R¹² is hydrogen see for example WO2006030610, US2005049419, and US2005/0054701 which are incorporated by reference herein. 6-[(4-bromo-2-chlorophenyl)amino]-7-fluoro-3-methyl-1,2-benzisoxazole-5-carboxylic acid was prepared using methods similar to those disclosed in WO2006030610, US2005049419, and US2005/0054701.

An intermediate of Formula IV(a) or IV(b):

where R⁷, X, R¹⁰, R¹², and R¹⁴ are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art.

An intermediate of Formula V(a) or V(b):

where R⁷, X, R¹⁰, R¹², R¹⁴, and R¹⁹ are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular the halo precursor of V(a) can be prepared using, for example, WO2003101968 and WO2002083648 which are incorporated by reference herein. In particular the halo precursor of V(b) can be prepared using, for example, US2004192653, US2004180896, US2004176325 which are incorporated by reference herein. The halo precursors are then reacted with an appropriate aniline to yield the intermediates of Formula V(a) and V(b).

An intermediate of Formula VI(a) or VI(b):

where R⁷, X, R¹⁰, R¹², and R¹⁴ are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, for VI(b) see for example WO2000042022 and WO2001005390 which are incorporated by reference herein.

An intermediate of Formula VII(a) or VII(b):

where R⁷, X, R¹⁰, R¹², and R¹⁴ are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. For intermediate VII(b) see, for example, WO2001005390 and WO2000042022 which are incorporated by reference herein.

An intermediate of Formula VIII(a) or VIII(b):

where R⁷, X, R¹⁰, R¹², R¹⁴, and R¹⁹ are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular for formula VIII(b) where R¹⁰ is halo (particularly fluoro), R¹² is hydrogen, R¹⁴ is hydrogen, and R¹⁹ is hydrogen or alkyl (particularly methyl) or alkenyl (particularly allyl), see WO 05/023251, WO2005009975, and WO2001005390 which are incorporated by reference herein. In particular for VIII(a) where X is halo (particularly chloro or fluoro) or alkyl (particularly methyl), R⁷ is halo (particularly iodo, bromo, or chloro) or haloalkoxy (particularly trifluormethoxy), R¹⁰ is halo (particularly fluoro or chloro), R¹⁴ is hydrogen or alkyl (particularly methyl), and R¹⁹ is hydrogen or alkyl (particularly methyl), see for example US 2004/0116710, WO 03/077914, WO 03/077855, WO 00/42022, WO2005009975, and WO2001005390 which are incorporated by reference herein. The following intermediates were prepared using similar procedures described in US 2004/0116710, WO 03/077914, WO 03/077855, WO 00/42022, WO2005009975, and WO2001005390: 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazole-6-carboxylic acid and 4-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-benzimidazole-6-carboxylic acid.

An intermediate of Formula IX:

where R⁷, X, R¹⁰, R¹², R¹⁴, and R¹⁶ are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, where R¹⁰ is hydrogen or halo (particularly chloro or fluoro); R¹² is hydrogen; R¹⁴ is hydrogen, amino, alkylamino, or dialkylamino; R¹⁶ is hydrogen; X is halo (particularly chloro); and R⁷ is halo (particularly bromo) see for example WO 05/023759, US 2005/0054701, US 2006030610, US 2005049419, and US 2005049276 which are incorporated by reference herein. The following intermediates were prepared using similar procedures as those described in WO 05/023759, as well as US 2006030610 and US 2005/0054701: 7-[(4-bromo-2-chlorophenyl)amino]-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid and 8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid. The following intermediates can be prepared using similar procedures described in the references given above: 8-Fluoro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid and 7-[(4-Bromo-2-fluorophenyl)amino]-8-fluoroimidazo[1,2-a]pyridine-6-carboxylic acid.

An intermediate of Formula X(a) and X(b):

where R⁷, X, R¹⁰, R¹², and R¹⁴ are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, where R¹⁰ is hydrogen, halo (specifically chloro), or alkyl (specifically methyl), R¹² is hydrogen, and R¹⁴ is hydrogen, halo (specifically bromo), see for example WO 06/045514 which is incorporated by reference herein. To prepare the intermediate of Formula X(b), the nitrogen in the pyridine ring of X(a) can then be oxidized with an agent such as MCPBA or H₂O₂. The following X(a) and X(b) intermediates were prepared using similar methods as disclosed in WO 06/045514: 3-[(2-Fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid and 3-[(2-Fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid 1-oxide. The following X(a) intermediates can be prepared using similar methods as disclosed in WO 06/045514: 2-Fluoro-3-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid and 3-[(4-Bromo-2-fluorophenyl)amino]pyridine-4-carboxylic acid.

An intermediate of Formula XI(a):

where R⁷, X, R¹⁰, R¹², and R¹⁴ are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, where R¹⁰ is hydrogen, R¹² is hydrogen or halo (particularly chloro or fluoro), R¹⁴ is amino or halo (particularly chloro), X is halo (particularly chloro), and R⁷ is halo (particularly bromo) see for example US 2005/0054701, US 200549419, and US 2006030610 which are incorporated by reference herein. The intermediate of Formula XI(b) can be prepared by oxidizing the nitrogen in the pyridine ring of XI(a) with an agent such as MCPBA or H₂O₂.

An intermediate of Formula XII:

where R⁷, X, R¹⁰, R¹², R¹⁴, and R¹⁶ are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, see for example WO 05/051302 which is incorporated by reference herein. The following intermediates can be prepared using similar methods as disclosed in WO 05/051302:

-   8-Fluoro-7-[(2-fluoro-4-iodophenyl)amino]-4-methylcinnoline-6-carboxylic     acid; -   7-[(4-Bromo-2-chlorophenyl)amino]-8-fluoro-4-methylcinnoline-6-carboxylic     acid; -   7-[(4-Bromo-2-fluorophenyl)amino]-8-fluoro-4-methylcinnoline-6-carboxylic     acid; and -   7-[(4-Bromo-2-fluorophenyl)amino]cinnoline-6-carboxylic acid.

An intermediate of Formula XIII:

where R⁷, X, R¹⁰, R^(10a), and Y¹ are as defined in the Summary of the Invention for Group C can be prepared using procedures known to one of ordinary skill in the art, including for example the procedures in US 05/0256123, Wallace, E. M. et al. J. Med. Chem. 2006, 49, 441-4, WO 2005000818, and WO 2005051301 (where Y¹ is carbon) which are incorporated by reference herein. 4-[(4-Bromo-2-fluorophenyl)amino]-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid was prepared using similar procedures to those disclosed in US 05/0256123 and WO 2005051301. 4-Chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid was prepared using similar procedures to those disclosed in US 2005256123. The following intermediates can be prepared using the methods disclosed in the above references:

-   4-[(2-Fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic     acid; -   4-[(4-Bromo-2-chlorophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic     acid; -   4-[(4-Bromo-2-fluorophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic     acid; -   4-[(4-Bromo-2-chlorophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic     acid; -   4-[(4-Bromo-2-chlorophenyl)amino]-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic     acid; and -   4-[(4-Bromo-2-fluorophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic     acid.

An intermediate of Formula XIV:

where R⁷, X, R¹⁰, and R¹⁴ are as defined in the Summary of the Invention for Group B can be prepared using procedures' known to one of ordinary skill in the art. In particular, see for example WO 05/051302 which is incorporated by reference herein.

An intermediate of Formula XVI

where X and R⁷ are as defined in the Summary of the Invention for a Compound of Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, see for example WO 2001005390 and WO 2000042022 for procedures that can be used to prepare the following: 5-[(2-Fluoro-4-iodophenyl)amino]-1H-benzotriazole-6-carboxylic acid; 5-[(2-Fluoro-4-iodophenyl)amino]-1-methyl-1H-benzotriazole-6-carboxylic acid; and 4-Fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1H-benzotriazole-6-carboxylic acid.

An intermediate of Formula XVII

where X and R⁷ are as defined in the Summary of the Invention for a Compound of Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, see Example 29.

An intermediate of Formula XVIII(a) or XVIII(b)

where X, R⁷, R⁴⁰, and R^(40a) are as defined in the Summary of the Invention for a Compound of Group D can be prepared using procedures known to one of ordinary skill in the art. In particular, the halo precursors to XVIII(a) and XVIII(b)

respectively can be prepared using procedures similar to those described in Machon and Dlugosz Acta Poloniae Pharmaceutica 1983, 40(1), 1-6 and von Angerer, Science of Synthesis 2004, 16, 379-572 (General Review written in English). The halo precursors are then reacted with

using procedures known to one of ordinary skill in the art and the synthetic methods disclosed herein. The following intermediates can be prepared as described above: 6-[(2-fluoro-4-iodophenyl)amino]-2-oxo-1,2-dihydropyrimidine-5-carboxylic acid and 4-[(2-fluoro-4-iodophenyl)amino]-2-oxo-1,2-dihydropyrimidine-5-carboxylic acid.

An intermediate of Formula XIX

where X and R⁷ are as defined in the Summary of the Invention for a Compound of Group C can be prepared using methods known to one of ordinary skill in the art. In particular see US 2005049276.

An intermediate of Formula XX

where X and R⁷ are as defined in the Summary of the Invention for a Compound of Group C can be prepared using methods known to one of ordinary skill in the art. In particular see US 2005049276.

The synthesis of azetidines substituted at the 3-position can be conveniently carried out according to Scheme 1:

starting from the N-diphenylmethyl protected azetidin-3-ol (1), readily prepared by reaction of epichlorohydrin and diphenylmethylamine (Chatterjee, Shym S.; Triggle, D. J. Chemical Communications (London) 1968, 2, 93). Protecting group exchange, from Boc to CBz, on the azetidine is carried out according to literature protocols (Greene, T. W., Wuts, P. G. Protective Groups in Organic Synthesis, Wiley-Interscience) and subsequent oxidation to the azetidinone (2) where P is CBz provides a useful intermediate for the preparation of compounds of the invention.

For example, the ketone intermediates of formula 2 can be broadly functionalized at the 3-position according to Scheme 2.

An intermediate of formula (3), where R⁴ is as defined in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D can be prepared by reacting the intermediate 2 with Grignard reagents or other organometallic species of formula 17, such as organolithiums. Alternatively, the intermediate 2 can be reacted with nitroalkane anions of formula 18 prepared in-situ as in the Henry reaction (The Henry reaction, recent examples: Luzzio, F. A. Tetrahedron 2001, 57(6), 915-945) to give (4) where R⁴′ is hydrogen or alkyl optionally substituted as described for R⁴ in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D. Alternatively, the intermediate 2 can be reacted with ketone or aldehyde anions of formula 19 in a Claisen-type condensation to give (5) where R⁴′ is alkyl optionally substituted as described for R⁴ in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D and R⁴″ is hydrogen or R⁴′. In addition, 2 can be reacted with Wittig reagents of formula 20 (where R′ and R″ are independently hydrogen, alkyl, alkenyl, aryl, or heteroaryl and the alkyl, alkenyl, aryl, and heteroaryl are optionally substituted as described for R⁴ in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D) to prepare intermediates of formula 6, which are also useful as precursors for compounds of the invention.

According to Scheme 3, intermediates of formula (6) where (R′ and R″ are hydrogen and P is a nitrogen-protecting group such as CBz or Boc)

can be further converted to the corresponding epoxide (7) and subsequent reaction with a suitable nitrogen base or other nucleophiles may be carried out to give access to a broad range of azetidin-3-ol derivatives such as (8), where R⁸ and R^(8′) are as defined in the Summary of the Invention.

In some cases the preparation of optically pure compounds is desired where the azetidine contains one or more stereocenters. Numerous techniques for the preparation of optically pure compounds through both resolution techniques and asymmetric synthesis are well known in the art. In one such case, an asymmetric synthesis methodology can be employed where an azetidine precursor of formula (2) is reacted with an intermediate of formula 21 where R′ is not hydrogen, as depicted in Scheme 4.

One such useful approach makes use of Evans oxazolidinone methodology (Diastereoselective aldol condensation using a chiral oxazolidinone auxiliary. Gage, James R.; Evans, David A. Organic Syntheses 1990, 68, 83-91). The condensation of an azetidinone (2) with the a chiral oxazolidinone in the presence of a base such as LDA affords an intermediate oxazolidinone (9), where P is a nitrogen-protecting group such as CBz or Boc, with diastereoselectivity. Treatment with lithium hydroxide in aqueous hydrogen peroxide gives carboxylic acid (10) which can be subject to Curtius rearrangement to provide the chiral oxazolidinone (11) then carried forward as required to a useful intermediate (12). Further protecting group manipulation and derivatization as required can be employed to prepare compounds of Formula I.

Alternatively, a racemic mixture of an intermediate of formula (13), useful to prepare a compound of Formula I where R³ is hydroxy and R⁴ is heterocycloalkyl (in particular, where R⁴ is a N-protected piperidine), can be prepared according to Scheme 5.

In the reaction schemes P¹ and P² are orthogonal nitrogen-protecting groups. For example, P¹ is Boc and P² is CBz or P¹ is CBz and P² is Boc. The reaction is carried out in-situ by treating 22 to generate the lithated amine and by subsequently treating it with a ketone such as (2) according to the method of Peter Beak (Beak, Peter; Lee, Won Koo α-Lithioamine synthetic equivalents: syntheses of diastereoisomers from the Boc-piperidines. Journal of Organic Chemistry 1990, 55(9), 2578-80). The racemate (13) thus prepared can be resolved by functionalization, as depicted in Scheme 6, with a chiral acid such as the readily-available Mosher acid (14).

The resulting diastereomeric esters (15) can be separated by chromatographic means and then carried forward individually as the enantiomerically pure intermediates (R)-(16) and (S)-(16).

Compounds of the Invention can be prepared by reacting an intermediate of Formula II, III(a), III(b), IV(a), IV(b), V(a), V(b), VI(a), VI(b), VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a), XI(b), XII, XIII, XIV, XVI, XVII, XVIII(a), XVIII(b), XIX, or XX with intermediate 17 according to Scheme 7:

The reaction is carried out in a solvent such as DMF, THF, or DCM in the presence of a base such as DIPEA, N-methylmorpholine, DMAP, or triethylamine and optionally in the presence of a coupling agent such as PyBOP, HBTU, or EDCI.

Alternatively an intermediate of Formula II, III(a), III(b), IV(a), IV(b), V(a), V(b), VI(a), VI(b), VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a), XI(b), XII, XIII, XIV, XVI, XVII, XVIII(a), XVIII(b), XIX, or XX can be converted into an acid halide according to Scheme 8

where X² is halo, such as chloro or fluoro, and all other groups are as defined in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D. The reaction is carried out in a solvent such as dioxane, THF, or DCM in the presence of a base such as DIPEA, sodium bicarbonate. The acid halide of formula 18 can then be reacted with an azetidine intermediate of formula 17 to prepare a compound of Formula I.

Synthetic Examples

Generally, the compounds listed below were identified by LC-MS, and/or isolated, and characterized by ¹H-NMR (most typically 400 MHz). Liquid chromatography-mass spectral (LC-MS) analyses were performed using at least one of: a Hewlett-Packard Series 1100 MSD, an Agilent 1100 Series LC/MSD (available from Agilent Technologies Deutschland GmbH of Waldbronn Germany), or a Waters 8-Channel MUX System (available from Waters Corporation of Milford, Mass.). Compounds were identified according to either their observed mass [MH⁺] or [MNa⁺] ion (positive mode) or [MH⁻] ion (negative mode). ¹H-NMR data for compounds was taken with a Varian AS400 Spectrometer (400 MHz, available from Varian GmbH, Darmstadt, Germany). Starting materials and intermediates used to prepare a compound of the invention are either commercially available or can be prepared by one of ordinary skill in the art.

Reference 1 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride

To a stirred mixture of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (12 g, 30.5 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, in dichloromethane (70 mL) at 0° C. was added pyridine (2.5 mL, 30.8 mmol) followed by dropwise addition of cyanuric fluoride (2.8 mL, 33.6 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane (100 mL). The aqueous layer was extracted once with dichloromethane (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product as a brownish solid. Crude product was purified by flash chromatography (plug, 25% ethyl acetate in hexanes) to afford 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride as a beige solid (11.8 g, 97% yield). ¹H NMR (400 MHz, CD₃OD): 8.41 (s, 1H), 7.80-7.81 (m, 1H), 7.52 (dd, 1H), 7.43-7.47 (m, 1H), 6.96-7.03 (m, 1H), 6.85-6.92 (m, 1H).

Reference 2 2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorobenzoic acid

To a solution of 2,3,4-trifluorobenzoic acid (1 g, 5.68 mmol) and 4-bromo-2-chloroaniline (1.2 g, 5.68 mmol) in acetonitrile (10 mL) was added lithium amide (0.39 g, 17.04 mmol) and the reaction stirred at 60° C. for 1.5 hours. The mixture was cooled to room temperature and then to 0° C. and acidified with aq. hydrochloric acid. The obtained precipitate was collected by filtration and washed with cold water and dried in vacuo to afford 2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorobenzoic acid (1.92 g, 94% yield) as a beige solid. MS (EI) for C₁₃H₇BrClF₂NO₂: 363 (MH⁺).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, 2-[(4-iodo-2-fluorophenyl)amino]-3-fluorobenzoic acid was prepared. MS (EI) for C₁₃H₈F₂₁NO₂: 376 (MH⁺).

Reference 3 Phenylmethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate

To a solution of azetidin-3-ol hydrochloride in tetrahydrofuran (90 mL) and water (10 mL) was added triethylamine (15 mL, 0.106 mol) followed by slow addition of benzyl chloroformate (8.0 mL, 0.056 mol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours then partitioned with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO₂, 25-50% ethyl acetate in hexanes) to afford phenylmethyl 3-hydroxyazetidine-1-carboxylate (3.56 g, 33% yield) as a clear and colorless oil. ¹H NMR (400 MHz, CDCl₃): 7.36-7.31 (m, 5H), 5.09 (s, 2H), 4.64-4.57 (m, 1H), 4.22 (dd, 2H), 3.88 (dd, 2H), 2.61 (d, 1H, J=4.0 Hz). MS (EI) for C₁₁H₁₃NO₃: 208 (MH⁺).

To a solution of phenylmethyl 3-hydroxyazetidine-1-carboxylate (3.5 g, 0.0168 mol) in dichloromethane (100 mL) was added Dess-Martin periodinane (10.7 g, 0.0.25 mol) at room temperature and stirred for 5 h. The reaction mixture was quenched with 1:1 ratio of saturated aqueous sodium bicarbonate and 1M sodium thiosulfate (200 mL) and then partitioned with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford phenylmethyl 3-oxoazetidine-1-carboxylate (3.43 g, 99% yield) as a clear and colorless oil without further purification. ¹H NMR (400 MHz, CDCl₃): 7.39-7.31 (m, 5H), 5.17 (s, 2H), 4.77 (s, 4H). MS (EI) for C₁₁H₁₁NO₃: 205 (M⁺).

A suspension of methyltriphenylphosphonium bromide (23.0 g, 0.0649 mol) and potassium tert-butoxide (7.3 g, 0.0649 mol) in diethyl ether (140 mL) was stirred at room temperature for 20 min, and then heated to 35° C. for 1 h. To this bright yellow reaction mixture was slowly added a dilute solution of phenylmethyl 3-oxoazetidine-1-carboxylate (3.33 g, 0.0162 mol) in diethyl ether (50 mL). The reaction mixture was stirred at 35° C. for 12 hours then filtered through a bed of celite and rinsed with ethyl ether. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO₂, 5-10% ethyl acetate in hexanes) to afford phenylmethyl 3-methylideneazetidine-1-carboxylate (2.46 g, 75% yield) as a clear and colorless oil). ¹H NMR (400 MHz, CDCl₃): 7.27-7.22 (m, 5H), 5.02 (s, 2H), 4.93-4.90 (m, 2H), 4.48-4.47 (m, 4H). MS (EI) for C₁₂H₁₃NO₂: 203 (M⁺).

To a solution of phenylmethyl 3-methylideneazetidine-1-carboxylate (2.46 g, 0.0121 mol) in chloroform (100 mL) was added 3-chloroperoxybenzoic acid (12.5 g, 0.0726 mol) at 0° C. The reaction mixture was allowed to warm up to room temperature over a period of 12 hours then quenched with 1 M sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1). The layers were separated and the organic layer was dried over anhydrous magnesium sulfate then concentrated. The residue was purified by flash chromatography (5-15% ethyl acetate in hexanes) to afford phenylmethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (2.2 g, 83% yield) as clear and colorless oil. ¹H NMR (400 MHz, CDCl₃): 7.37-7.29 (m, 5H), 5.12 (s, 2H), 4.35-4.26 (m, 4H), 2.85 (s, 2H). MS (EI) for C₁₂H₁₃NO₃: 220 (MH⁺).

Reference 4 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid was prepared using procedures similar to those disclosed in US 2005256123.

To a solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (350 mg, 1.855 mmol) and 2-fluoro-4-iodoaniline (1.06 g, 4.453 mmol) in tetrahydrofuran (13.3 mL) was sparged with nitrogen for 5 minutes followed by the slow addition of lithium bis(trimethylsilyl)amide, 1.0 M in THF (7.4 mL). The reaction mixture stirred for an additional 4 hours at room temperature. The mixture was quenched with 1 N HCl and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N aqueous HCl. The aqueous layer was extracted (3×) with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (939 mg, 100% yield). ¹H NMR (CDCl₃): 7.27 (dd, 1H), 7.21 (d, 1H), 6.54 (t, 1H), 4.84 (broad s, 2H), 2.09 (s, 1H), 1.26 (t, 3H); MS (EI) for C₁₂H₉N₃O₃FI: 389 (MH⁺).

A solution of 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (939 mg, 2.413 mmol) in dichloromethane (60 mL) in the presence of dimethylformamide (8.0 mL) was cooled to 0° C. Malonyl chloride (1.26 mL, 14.48 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was evaporated and partitioned between ethyl acetate and 1M aqueous ammonium chloride. The aqueous layer was extracted 1× with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl chloride. This crude material was taken into the next step without further purification. MS (EI) for C₁₂H₈N₃O₂ClFI: 408 (MH⁺).

To a solution of 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl chloride in methanol (15 mL) and benzene (12 mL) was added dropwise trimethylsilyl diazomethane (1 mL) and stirred at room temperature for 15 minutes. The reaction mixture was quenched with acetic acid and evaporated. The residue was partitioned between ethyl acetate and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel chromatography column (7:3 hexanes/ethyl acetate) to afford methyl 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (84.9 mg, 8.7% yield). ¹H NMR (CDCl₃): 7.49-7.56 (m, 3H), 7.12 (t, 1H), 6.13 (d, 1H), 4.00 (s, 3H), 3.83 (s, 3H); MS (EI) for C₁₃H₁₁N₃O₃FI: 404 (MH⁺).

Methyl 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (84.9 mg, 0.211 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (2.5 mL) and water (2.5 mL). Aqueous 2 M lithium hydroxide (200 μL) was added at room temperature. After 10 minutes, the reaction mixture was heated to 50° C. for 30 minutes and continued to stir at room temperature for 16 hours at which time the solvents were evaporated. The residue was made acidic with 2 M aqueous hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic layer separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (54.0 mg, 66% yield). MS (EI) for C₁₂H₉N₃O₃FI: 390 (MH⁺).

Reference 5 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate

To a solution of 1,1-dimethylethyl piperidine-1-carboxylate (0.50 g, 2.7 mmol) in anhydrous diethyl ether (9.0 mL) under anhydrous nitrogen gas was added N,N,N′,N′-tetramethylethane-1,2-diamine (0.41 mL, 2.7 mmol), and the solution was cooled to −78° C. To this solution was added (2-methylpropyl)lithium (2.1 mL, 1.4 M in cyclohexane, 3.0 mmol) in small portions. To this anion solution was added phenylmethyl 3-oxoazetidine-1-carboxylate (1.0 g, 5.4 mmol), prepared using procedures as described in Reference 3, in anhydrous ether (2.0 mL), while maintaining the internal temperature at less than −60° C. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, and partitioned between water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether twice. The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.13 g (13%) of 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate. ¹H NMR (400 MHz, CDCl₃): 7.31 (m, 5H), 5.08 (s, 2H), 4.05 (d, 1H), 4.00 (d, 1H), 3.84 (d, 2H), 3.80 (broad s, 1H), 3.55 (broad s, 1H), 3.10 (broad s, 1H), 1.92 (m, 1H), 1.45-1.62 (m, 6H), 1.43 (s, 9H). MS (EI) for C₂₁H₃₀N₂O₅: 335 (M-tBu), 315 (M-OtBu).

Example 1 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (2.1 g, 5.3 mmol), prepared using procedures similar to those in U.S. Pat. No. 7,019,033, was taken into DMF (10 mL) followed by addition of PyBOP (2.6 g, 5.3 mmol) and the mixture was allowed to stir at room temperature over 15 minutes. Azetidin-3-ol hydrochloride (870 mg, 8.0 mmol) and DIPEA (1.85 mL, 11.2 mmol) was then added and the mixture was allowed to stir an additional hour at room temperature. The mixture was then partitioned with ethyl acetate and 0.5 M aqueous sodium hydroxide solution. The organic layer was then washed with water (3×) then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography using ethyl acetate:hexanes (5:1) eluent afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (2.09 g, 87% yield) as a colorless amorphous solid. ¹H NMR (400 MHz, CDCl₃): 8.47 (s, 1H), 7.39 (dd, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.78 (m, 1H), 6.63-6.57 (m, 1H), 4.74-4.67 (m, 1H), 4.43-4.39 (m, 2H), 4.20-3.96 (br d, 2H), 2.50 (d, 1H).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the compounds in Examples 1(a)-(e) were prepared.

Example 1(a)

1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}-carbonyl)azetidin-3-yl]-N,N-dimethylpyrrolidin-3-amine. The title compound was prepared by reacting 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid with N-methyl-N-(2-(pyridin-2-yl)ethyl)azetidin-3-amine. The azetidine intermediate was prepared using procedures similar to those described in Abdel-Magid, et. al., Tetrahedron Letters 1990, 31(39), 5595 starting with tert-butyl 3-oxoazetidine-1-carboxylate, which itself was prepared as described in Example 3. The title compound: ¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1H), 7.58 (m, 1H), 7.38 (d, 1H), 7.31 (m, 1H), 7.16 (m, 1H), 6.67 (m, 1H), 4.16 (m, 1H), 3.97 (m, 2H), 3.77 (m, 1H), 3.26 (br s, 4H), 2.63 (m, 1H), 2.42 (br s, 6H), 1.99 (br s, 1H), 1.74 (br s, 1H). MS (EI) for C₂₂H₂₄F₃IN₄O: 545 (MH⁺).

Example 1(b)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methyl-N-(2-pyridin-2-ylethyl)azetidin-3-amine. The title compound was prepared by reacting 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid with 1-(azetidin-3-yl)-N,N-dimethylpyrrolidin-3-amine. The azetidine intermediate was prepared using procedures similar to those described in Abdel-Magid, et. al., Tetrahedron Letters 1990, 31(39), 5595 starting with tert-butyl 3-oxoazetidine-1-carboxylate, which itself was prepared as described in Example 3. The title compound: ¹H NMR (400 MHz, CD₃OD): 8.50 (d, 1H), 7.94 (t, 1H), 7.50-7.30 (m, 5H), 7.07 (q, 1H), 6.66-6.61 (m, 1H), 4.52-4.48 (m, 2H), 4.31 (s, 2H), 4.23-4.18 (m, 1H), 3.48-3.46 (m, 2H), 3.17-3.13 (m, 2H), 2.88 (s, 3H); MS (EI) for C₂₄H₂₂F₃IN₄O: 567 (MH⁺).

Example 1(c)

6-(Azetidin-1-ylcarbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline: ¹H NMR (400 MHz, CDCl₃): 8.57 (s, 1H), 7.41-7.38 (dd, 1H), 7.34-7.31 (dt, 1H), 7.13-7.09 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.58 (m, 1H), 4.27 (b, 2H), 4.18 (b, 2H), 2.38-2.30 (p, 2H); MS (EI) for C₁₆H₁₂F₃IN₃O: 433 (MH⁺).

Example 1(d)

[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol: ¹H NMR (400 MHz, CDCl₃): 8.52 (s, 1H), 7.41-7.38 (dd, 1H), 7.34-7.31 (dt, 1H), 7.15-7.11 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.58 (m, 1H), 4.29-4.20 (m, 2H), 4.09 (b, 1H), 3.93 (b, 1H), 3.82-3.81 (d, 2H), 2.89-2.75 (m, 1H); MS (EI) for C₁₇H₁₄F₃IN₂O₂: 463 (MH⁺).

Example 1(e)

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylic acid: ¹H NMR (400 MHz, CDCl₃): 7.79 (b, 2H), 7.42-7.38 (dd, 1H), 7.34-7.32 (dt, 1H), 7.15-7.11 (m, 1H), 6.89-6.83 (m, 1H), 6.65-6.60 (m, 1H), 4.46-4.29 (m, 4H), 3.55-3.47 (m, 1H); MS (EI) for C₁₇H₁₂F₃IN₂O₃: 477 (MH⁺).

Example 2 N-[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2,N2-diethylglycinamide

A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (200 mg, 0.51 mmol), prepared using procedures similar to those in U.S. Pat. No. 7,019,033, PyBOP (256 mg, 0.51 mmol), commercially available tert-butyl azetidin-3-ylcarbamate (131 mg, 0.77 mmol) and N,N-diisopropylethylamine (180 μL, 1.02 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was partitioned between 5% aqueous lithium chloride and ethyl acetate. The organic portion was washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford 1,1-dimethylethyl [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (225 mg, 80% yield) as a colorless oil. ¹H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.60-7.55 (m, 2H), 7.38 (d, 1H), 7.30-7.26 (m, 1H), 7.20-7.13 (m, 1H), 6.71-6.66 (m, 1H), 4.37-4.20 (m, 2H), 4.18-4.06 (m, 1H), 3.98-3.93 (m, 1H), 3.82-3.75 (m, 1H), 1.37 (s, 9H). MS (EI) C₂₁H₂₁N₃O₃F₃I: 548 (MH⁺).

A solution of 1,1-dimethylethyl [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (113 mg, 0.20 mmol) and trifluoroacetic acid (500 μL) in dichloromethane (2 mL) was added stirred at room temperature for one hour then was partitioned between saturated aqueous sodium bicarbonate, and dichloromethane. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a colorless residue which was purified by column chromatography eluting with 10% methanol in dichloromethane to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (85 mg, 95% yield) as a white foam. ¹H NMR (400 MHz, CDCl₃): 8.53 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.46-4.39 (m, 2H), 3.98-3.75 (br m, 4H); MS (EI) for C₁₆H₁₃F₃IN₃O: 448 (MH⁺).

A solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (100 mg, 0.22 mmol), PyBOP (131 mg, 0.25 mmol), N,N-diisopropylethylamine (80 μL, 0.44 mol) and bromoacetic acid (35 mg, 0.25 mmol) in dimethylformamide (1 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the resultant residue was purified by column chromatography eluting with 80% ethyl acetate in hexanes to afford 2-bromo-N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]acetamide (102 mg, 82% yield) as a white foam. MS (EI) for C₁₈H₁₄BrF₃IN₃O₂: 568.

A solution of 2-bromo-N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]acetamide (30 mg, 0.05 mmol) and N,N-diethylamine (100 μL, excess) in dichloromethane (2 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and purified by preparative reverse phase HPLC (CH₃CN/H₂O with 0.1% TFA). Isolated product was concentrated in vacuo to afford N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2,N2-diethylglycinamide trifluoroacetate salt (13.0 mg, 38% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): 9.36 (br s, 1H), 9.25 (d, 1H), 8.60 (s, 1H), 7.60 (d, 1H), 7.40 (d, 1H), 7.33-7.27 (m, 1H), 7.22-7.15 (m, 1H), 6.73-6.66 (m, 1H), 4.54-4.40 (m, 2H), 4.25-4.20 (m, 1H), 4.04-3.82 (m, 4H), 3.17-3.12 (m, 4H), 1.18-1.15 (m, 6H); MS (EI) C₂₂H₂₄F₃IN₄O₂: 561 (MH⁺).

Using the same or analogous synthetic techniques and/or substituting with alternative reagents, the compounds in Examples 2(a)-(n) were prepared.

Example 2(a)

1,1-Dimethylethyl [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate: ¹H NMR (400 MHz, CDCl₃): 8.52 (br s, 1H), 7.40 (dd, 1H), 7.33 (dt, 1H), 7.13-7.07 (m, 1H), 6.80 (ddd, 1H), 6.61 (ddd, 1H), 5.01-4.88 (br, 1H), 4.55-4.37 (br, 4H), 4.05 (br d, 1H), 1.43 (s, 9H); MS (EI) for C₂₁H₂₁F₃IN₃O₃S: 548 (MH⁺).

Example 2(b)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine trifluoroacetate salt: ¹H NMR (400 MHz, CDCl₃): 8.53 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.46-4.39 (m, 2H), 3.98-3.75 (br m, 4H); MS (EI) for C₁₆H₁₃F₃IN₃O: 448 (MH⁺).

Example 2(c)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-methylpropanamide: ¹H NMR (400 MHz, DMSO): 8.60 (s, 1H), 8.38 (d, 1H), 7.59 (d, 1H), 7.38 (d, 1H), 7.32-7.28 (m, 1H), 7.18-7.13 (m, 1H), 6.72-6.66 (m, 1H), 4.45-4.35 (m, 1H), 4.18-3.77 (m, 4H), 2.36-2.28 (m, 1H), 0.99 (d, 6H); MS (EI) C₂₀H₁₉F₃IN₃O₂: 518 (MH⁺).

Example 2(d)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]formamide: ¹H NMR (400 MHz, DMSO): 8.69 (d, 1H), 8.58 (s, 1H), 8.02 (s, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.31-7.27 (m, 1H), 7.19-7.13 (m, 1H), 6.70-6.66 (m, 1H), 4.55-4.46 (m, 1H), 4.42-4.36 (m, 1H), 4.20-4.16 (m, 1H), 4.01-3.97 (m, 1H), 3.82-3.79 (m, 1H); MS (EI) C₁₇H₁₃F₃IN₃O₂: 476 (MH⁺).

Example 2(e)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-3,4-dihydroxybutanamide: ¹H NMR (400 MHz, DMSO): 8.60 (s, 1H), 8.47 (d, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.31-7.28 (m, 1H), 7.20-7.14 (m, 1H), 6.72-6.66 (m, 1H), 4.45-4.35 (m, 2H), 4.18-4.14 (m, 1H), 4.00-3.92 (m, 1H), 3.84-3.78 (m, 2H), 3.31-3.18 (m, 2H), 2.38-2.18 (m, 1H), 2.09-2.03 (m, 1H); MS (EI) C₂₀H₁₉F₃IN₃O₄: 550 (MH⁺).

Example 2(f)

methyl [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate: ¹H NMR (400 MHz, DMSO): 8.58 (s, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.35-7.27 (m, 1H), 7.20-7.13 (m, 1H), 6.71-6.66 (m, 1H), 4.38-4.25 (m, 2H), 4.17-4.12 (m, 1H), 4.00-3.97 (m, 1H), 3.83-3.78 (m, 1H), 3.53 (s, 3H); MS (EI) C₁₈H₁₅F₃IN₃O₃: 506 (MH⁺).

Example 2(g)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamide trifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 8.64 (s, 1H), 8.54 (d, 1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.32-7.29 (m, 1H), 7.21-7.15 (m, 1H), 6.72-6.66 (m, 1H), 4.54-4.28 (m, 2H), 4.19-4.15 (m, 1H), 4.06-4.00 (m, 1H), 3.91-3.84 (m, 1H), 3.44-3.24 (m, 2H), 3.16-2.92 (m, 6H), 2.78 (s, 3H), 2.62-2.50 (m, 2H); MS (EI) C₂₃H₂₅F₃IN₅O₂: 588 (MH⁺).

Example 2(h)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N N-bis(2-hydroxyethyl)glycinamide trifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 9.19 (d, 1H), 7.60 (d, 1H), 7.41 (d, 1H), 7.31-7.27 (m, 1H), 7.21-7.15 (m, 1H), 6.73-6.66 (m, 1H), 4.51-4.40 (m, 2H), 4.23-4.18 (m, 1H), 4.05-3.98 (m, 3H), 3.86-3.82 (m, 1H), 3.75-3.69 (m, 3H), 3.32 (br s, 4H) C₂₂H₂₄F₃IN₄O₄: 593 (MH⁺).

Example 2(i)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-piperidin-1-ylacetamide trifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 9.20 (d, 1H), 7.60 (d, 1H), 7.41 (d, 1H), 7.31-7.27 (m, 1H), 7.21-7.15 (m, 1H), 6.73-6.66 (m, 1H), 4.52-4.40 (m, 2H), 4.24-4.18 (m, 1H), 4.05-4.00 (m, 1H), 3.87-3.80 (m, 3H), 3.40-3.32 (m, 2H), 3.00-2.91 (m, 2H), 1.82-1.66 (m, 6H); MS (EI) C₂₃H₂₄F₃IN₄O₂: 573 (MH⁺).

Example 2(j)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N3-(2-hydroxyethyl)-N3-methyl-beta-alaninamide hydrochloride: ¹H NMR (400 MHz, DMSO): 9.36 (br s, 1H), 8.86 (d, 1H), 8.60 (s, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.32-7.26 (m, 1H), 7.21-7.14 (m, 1H), 6.72-6.66 (m, 1H), 5.35-5.33 (m, 1H), 4.48-4.37 (m, 2H), 4.20-4.15 (m, 1H), 4.02-3.96 (m, 1H), 3.84-3.79 (m, 1H), 3.74-3.68 (m, 2H), 3.42-3.06 (m, 4H), 2.75 (s, 3H), 2.65-2.60 (m, 2H); MS (EI) C₂₂H₂₄F₃IN₄O₃: 577 (MH⁺).

Example 2(k)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N3,N3-bis(2-hydroxyethyl)-beta-alaninamide hydrochloride: ¹H NMR (400 MHz, DMSO): 9.39 (br s, 1H), 8.91 (d, 1H), 8.61 (s, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.31-7.27 (m, 1H), 7.21-7.14 (m, 1H), 6.72-6.66 (m, 1H), 5.31 (br s, 2H), 4.46-4.36 (m, 2H), 4.20-4.15 (m, 1H), 4.02-3.97 (m, 1H), 3.85-3.72 (m, 5H), 3.30-3.17 (m, 4H), 2.68-2.63 (m, 2H); MS (EI) C₂₃H₂₆F₃IN₄O₄: 607 (MH⁺).

Example 2(m)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2-methylglycinamide trifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 9.09 (d, 1H), 8.69 (br s, 2H), 8.60 (s, 1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.31-7.27 (m, 1H), 7.22-7.15 (m, 1H), 6.73-6.66 (m, 1H), 4.54-4.41 (m, 2H), 4.25-4.19 (m, 1H), 3.99-3.96 (m, 1H), 3.84-3.78 (m, 1H), 3.72-3.67 (m, 2H), 2.58-2.54 (m, 3H); MS (EI) C₁₉H₁₈F₃IN₄O₂: 519 (MH⁺).

Example 2(n)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]glycinamide trifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 8.59 (s, 1H), 8.46 (br s, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.32-7.28 (m, 1H), 7.20-7.13 (m, 1H), 6.72-6.66 (m, 1H), 4.49 (br s, 1H), 4.40-4.35 (m, 1H), 4.18-4.13 (m, 1H), 4.05-4.01 (m, 1H), 3.86-3.81 (m, 1H), 3.07 (s, 2H); MS (EI) C₁₈H₁₆F₃IN₄O₂: 505 (MH⁺).

Example 3 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(morpholin-4-ylmethyl)azetidin-3-ol

A mixture of 3-azetidinol hydrochloride (10 g, 91 mmol), di-tert-butyl dicarbonate (18.8 g, 86.3 mmol) and sodium bicarbonate (15.3 g, 182 mmol) in dioxane:water (400 mL, 1:1) was stirred at room temperature for 15 hours. The organic portion was removed in vacuo and the aqueous portion was extracted with ethyl acetate three times. The combined organic portion was washed with 5% aqueous HCl, water, brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford 12.8 g, 74 mmol (81%) of 1,1-dimethylethyl 3-hydroxyazetidine-1-carboxylate as a colorless oil without further purification. ¹H NMR (400 MHz, DMSO): 5.62 (d, 1H), 4.40-4.33 (m, 1H), 4.02-3.95 (m, 2H), 3.62-3.54 (m, 2H), 1.37 (s, 9H). GC/MS for C₈H₁₅NO₃: 173.

A solution of oxalyl chloride (545 μL, 6.36 mmol) in dichloromethane (25 mL) was cooled to −78° C. While maintaining an internal temperature of −78° C., the dropwise addition of DMSO (903 μL, 12.7 mmol) followed by 1,1-dimethylethyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.78 mmol in 30 mL of dichloromethane) and finally triethylamine (3.25 mL, 23.1 mmol in 20 mL of dichloromethane) was performed. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The reaction mixture was diluted with water and partitioned and the organic portion was washed twice with water. The combined aqueous portion was extracted once with dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 893 mg, 5.20 mmol (90%) of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate as a colorless oil, which solidified upon standing. ¹H NMR (400 MHz, DMSO): 4.67 (s, 4H), 1.42 (s, 9H). GC/MS for C₈H₁₃NO₃: 171.

A mixture of potassium tert-butoxide (15.5 g, 137 mmol) and methyltriphenylphosphine bromide (49 g, 137 mmol) in diethyl ether (300 mL) was stirred at room temperature for 1 hour, followed by the addition of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (10 g, 58 mmol in 100 mL diethyl ether). The mixture was stirred at 35° C. for 2 hours and then allowed to cool to room temperature. The mixture was filtered through a pad of celite, washing with diethyl ether. The filtrate was partitioned with water and washed twice with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil which was purified by column chromatography. Eluting with 10% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 9.80 g, 58 mmol (100%) of 1,1-dimethylethyl 3-methylideneazetidine-1-carboxylate as a colorless oil. ¹H NMR (400 MHz, DMSO): 5.05-4.85 (m, 2H), 4.95-4.63 (m, 4H), 1.45 (s, 9H). GC-MS for C₉H₁₅NO₂: 169.

To a solution of 1,1-dimethylethyl 3-methylideneazetidine-1-carboxylate (2.96 g, 17.5 mmol) in chloroform (180 mL) was added 3-chloroperoxybenzoic acid (77%, 13.9 g, 62.0 mmol), and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate and saturated sodium bicarbonate solutions. The organic portion was isolated, dried over sodium sulfate, filtered and concentrated to give an oily residue which was then purified by flash chromatography (15-50% ethyl acetate-hexanes) to give 1,1-dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (1.65 g, 51%), GC-MS for C₉H₁₅NO₃: 185.

1,1-Dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (51 mg, 0.28 mmol) was taken into THF (1 mL) followed by addition of morpholine (123 μL, 1.4 mmol) and the mixture was stirred for one hour at room temperature. The solution was then concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed once with water then brine and the organic layer dried over anhydrous sodium sulfate. Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents. The combined pure fractions were concentrated and the residue treated with neat TFA (1 mL) for 5 minutes then concentrated. The residue was taken into methanol (2 mL) and basified to pH>10 by addition of Biorad AG-1X hydroxide form resin. Filtration and concentration afforded 3-(morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 24% yield) as a colorless oil. ¹H NMR (400 MHz, CD₃OD): 3.69-3.66 (m, 4H), 3.55 (d, 2H), 3.49 (d, 2H), 2.66 (s, 2H), 2.57-2.55 (m, 4H).

3-(Morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 0.07 mmol) was taken into DMF (1 mL) followed by addition of DIPEA (35 μL, 0.21 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (28 mg, 0.07 mmol), prepared using procedures similar to those described in Reference 1, and the mixture was stirred for 30 minutes at room temperature. The solution was then concentrated in vacuo and the residue purified by preparative reverse phase HPLC. Lyophillization of the combined fractions gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(morpholin-4-ylmethyl)azetidin-3-ol trifluoroacetate salt (6.3 mg) as a colorless amorphous solid. ¹H NMR (400 MHz, CD₃OD): 7.48 (d, 1H), 7.36 (d, 1H), 7.33-7.29 (m, 1H), 7.08-7.02 (m, 1H), 6.65-6.60 (m, 1H), 4.39 (br d, 1H), 4.24-4.18 (br, 2H), 4.08-3.96 (br m, 3H), 3.80 (br s, 2H), 3.51 (d, 2H), 3.40 (br s, 2H), 3.24 (br s, 2H).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds were prepared.

Example 3(a)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(pyrrolidin-1-ylmethyl)azetidin-3-ol: MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Example 3(b)

1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}piperidin-4-ol: MS (EI) for C₂₂H₂₃F₃IN₃O₃: 562 (MH⁺).

Example 3(c)

3-{[bis(2-hydroxyethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: MS (EI) for C₂₁H₂₃F₃IN₃O₄: 566 (MH⁺).

Example 3(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(4-methylpiperazin-1-yl)methyl]azetidin-3-ol: MS (EI) for C₂₂H₂₄F₃IN₄O₂: 561 (MH⁺).

Example 3(e)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(4-methyl-1,4-diazepan-1-yl)methyl]azetidin-3-ol: MS (EI) for C₂₃H₂₆F₃IN₄O₂: 575 (MH⁺).

Example 3(f)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[methyl(1-methylpyrrolidin-3-yl)amino]methyl}azetidin-3-ol: MS (EI) for C₂₃H₂₆F₃IN₄O₂: 575 (MH⁺).

Example 3(g)

3-(1,4′-bipiperidin-1′-ylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: MS (EI) for C₂₇H₃₂F₃IN₃O₂: 629 (MH⁺).

Example 3(h)

3-({4-[2-(diethylamino)ethyl]piperazin-1-yl}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: MS (EI) for C₂₇H₃₅F₃IN₃O₂: 647 (MH⁺).

Example 3(i)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyethyl)(methyl)amino]methyl}azetidin-3-ol: MS (EI) for C₂₀H₂₁F₃IN₃O₃: 536 (MH⁺).

Example 3(j)

3-(azetidin-1-ylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: MS (EI) for C₂₀H₁₉F₃IN₃O₂: 518 (MH⁺).

Example 3(k)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-ol: MS (EI) for C₂₀H₂₁F₃IN₃O₂: 520 (MH⁺).

Example 3(m)

3-(aminomethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: MS (EI) for C₁₇H₁₅F₃IN₃O₂: 478 (MH⁺).

Example 3(n)

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}acetamide: MS (EI) for C₁₉H₁₇F₃IN₃O₃: 520 (MH⁺).

Example 3(o)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethylethyl)amino]methyl}azetidin-3-ol: MS (EI) for C₂₁H₂₃F₃IN₃O₄: 534 (MH⁺).

Example 3(q)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(hydroxyamino)methyl]azetidin-3-ol: ¹H NMR (400 MHz, d₄-MeOH): 7.45 (2d, 1H), 7.35 (m, 1H), 7.28 (m, 1H), 7.03 (m, 1H), 6.63 (m, 1H), 4.32 (d, 1H), 4.05 (dd, 2H), 3.85 (d, 1H), 3.00 (s, 2H); MS (EI) for C₁₇H₁₅F₃IN₃O₃: 494 (MH⁺).

Example 3(r)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(methyloxy)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₄-MeOH): 7.45 (2d, 1H), 7.35 (m, 1H), 7.27 (m, 1H), 7.04 (m, 1H), 6.62 (m, 1H), 4.26 (d, 1H), 4.08 (d, 1H), 4.00 (d, 1H), 3.84 (d, 1H), 3.30 (s, 3H), 3.00 (d, 2H); MS (EI) for C₁₈H₁₇F₃IN₃O₃: 508 (MH⁺).

Example 3(s)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(ethyloxy)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₄-MeOH): 7.45 (2d, 1H), 7.34 (m, 1H), 7.26 (m, 1H), 7.03 (m, 1H), 6.63 (m, 1H), 4.26 (d, 1H), 4.12 (d, 1H), 4.00 (d, 1H), 3.84 (d, 1H), 3.61 (dd, 2H), 3.00 (s, 2H), 1.06 (t, 3H); MS (EI) for C₁₉H₁₉F₃IN₃O₃: 522 (MH⁺).

Example 3(t)

1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}guanidine acetate salt: ¹H NMR (400 MHz, d₄-MeOH): 7.46 (2d, 1H), 7.36 (m, 1H), 7.30 (m, 1H), 7.04 (m, 1H), 6.62 (m, 1H), 4.18 (d, 1H), 4.08 (d, 1H), 4.02 (d, 1H), 3.88 (1H), 3.40 (s, 2H); MS (EI) for C₁₈H₁₇F₃IN₅O₂: 520 (MH⁺).

Example 3(u)

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}benzenecarboximidamide hydrochloride: ¹H NMR (400 MHz, d₄-MeOH): 7.70 (d, 3H), 7.58 (m, 2H), 7.46 (dd, 1H), 7.36 (m, 1H), 7.31 (m, 1H), 7.04 (m, 1H), 6.62 (m, 1H), 4.28 (m, 1H), 4.15 (m, 2H), 3.96 (m, 1H), 3.78 (s, 2H); MS (EI) for C₂₄H₂₀F₃IN₄O₂: 581 (MH⁺).

Example 3(v)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(pyrimidin-2-ylamino)methyl]azetidin-3-ol hydrochloride: ¹H NMR (400 MHz, d₄-MeOH): 8.48 (s, 2H), 7.46 (2d, 1H), 7.36 (m, 1H), 7.28 (m, 1H), 7.04 (m, 1H), 6.85 (t, 1H), 6.61 (m, 1H), 4.24 (d, 1H), 4.06 (t, 2H), 3.87 (d, 1H), 3.75 (d, 2H); MS (EI) for C₂₁H₁₇F₃IN₅O₂: 556 (MH⁺).

Example 3(w)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(pyridin-2-ylamino)methyl]azetidin-3-ol hydrochloride: ¹H NMR (400 MHz, d₄-MeOH): 7.87 (dd, 1H), 7.85 (dd, 1H), 7.46 (2d, 1H), 7.36 (m, 2H), 7.06 (m, 2H), 6.89 (m, 1H), 6.61 (m, 1H), 4.53 (d, 2H), 4.46 (m, 1H), 4.28 (m, 1H), 4.16 (m, 1H), 3.96 (m, 1H); MS (EI) for C₂₂H₁₈F₃IN₄O₂: 555 (MH⁺).

Example 3(x)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(ethylamino)methyl]azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.61 (s, 2H), 7.59 (d, 1H), 7.40 (d, 1H), 7.36-7.33 (m, 1H), 7.23-7.18 (m, 1H), 6.71 (s, 2H), 4.31-4.26 (m, 1H), 4.13-4.05 (m, 2H), 3.88-3.84 (m, 1H), 3.21 (br m, 2H), 2.97-2.90 (m, 2H), 1.19 (t, 3H). MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 3(y)

3-[(cyclopropylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.99 (br s, 2H), 8.60 (s, 1H), 7.58 (d, 1H), 7.39 (d, 1H), 7.36-7.33 (m, 1H), 7.23-7.16 (m, 1H), 6.72 (s, 2H), 4.34-4.29 (m, 1H), 4.14-4.04 (m, 2H), 3.88-3.84 (m, 1H), 2.70-2.64 (m, 1H), 0.89 (br s, 2H), 0.74-0.69 (br s, 2H). MS (EI) for C₂₀H₁₉F₃IN₃O₂: 518 (MH⁺).

Example 3(z)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2,2,2-trifluoroethyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.60 (s, 1H), 7.58 (d, 1H), 7.38 (d, 1H), 7.35-7.30 (m, 1H), 7.22-7.17 (m, 1H), 6.72-6.67 (m, 1H), 4.25-4.19 (m, 1H), 4.07-3.98 (m, 2H), 3.86-3.77 (m, 2H), 3.19-3.09 (m, 2H). MS (EI) for C₁₉H₁₆F₆IN₃O₂: 560 (MH⁺).

Example 3(aa)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-1,2,3-triazol-1-ylmethyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.55 (s, 1H), 8.04 (s, 1H), 7.66 (s, 1H), 7.58 (d, 1H), 7.39 (d, 1H), 7.34-7.29 (m, 1H), 7.22-7.15 (m, 1H), 6.72-6.66 (m, 1H), 6.29 (s, 1H), 4.64 (s, 2H), 4.29-4.25 (m, 1H), 4.13-4.09 (m, 1H), 4.00-3.96 (m, 1H), 3.77-3.73 (m, 1H), 3.16 (d, 1H). MS (EI) for C₁₉H₁₅F₃IN₅O₂: 530 (MH⁺).

Example 3(bb)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2,2-dimethylpropyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.61 (s, 1H), 8.30 (s, 2H), 7.59 (d, 1H), 7.39 (d, 1H), 7.36-7.17 (m, 4H), 6.77-6.66 (m, 4H), 4.35-4.30 (m, 1H), 4.16-4.08 (m, 2H), 3.92-3.87 (m, 1H), 3.31-3.27 (m, 2H), 2.78-2.74 (m, 2H), 1.76 (s, 4H), 0.99 (s, 9H). MS (EI) for C₂₂H₂₅F₃IN₃O₂: 548 (MH⁺).

Example 3(cc)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(4-methylphenyl)ethyl]amino}methyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CDCl₃): 8.48 (s, 1H), 7.39 (dd, 1H), 7.31-7.34 (m, 1H), 7.08 (dd, 5H), 6.77-6.83 (m, 1H), 6.58-6.63 (m, 1H), 4.20 (br s, 1H), 4.01 (d, 1H), 2.87 (t, 4H), 2.75 (t, 4H), 2.5 (br s, 2H), 2.33 (s, 3H), 2.08 (s, 2H). MS (EI) for C₂₆H₂₅F₃IN₃O₂: 594 (M-H).

Example 3(dd)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2,3-dihydro-1H-inden-2-ylamino)methyl]azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CDCl₃): 8.48 (s, 1H), 7.40 (dd, 1H), 7.32-7.34 (m, 1H), 7.15-7.22 (m, 4H), 7.10-7.14 (m, 1H), 6.77-6.83 (m, 1H), 6.58-6.64 (m, 1H), 4.22 (br s, 1H), 4.04 (d, 1H), 3.57-3.63 (m, 1H), 3.17 (dd, 2H), 2.94 (s, 2H), 2.75 (dd, 2H), 2.48 (br s, 4H), 2.08 (s, 2H). MS (EI) for C₂₆H₂₃F₃IN₃O₂: 592 (M-H).

Example 3(ee)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1S,2S)-2-hydroxycyclopentyl]amino}methyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.46 (dd, 1H), 7.33-7.37 (m, 1H), 7.26-7.31 (m, 1H), 7.00-7.08 (m, 1H), 6.58-6.65 (m, 1H), 4.2 (t, 1H), 3.86-4.06 (m, 4H), 2.92-3.10 (m, 3H), 2.00-2.10 (m, 1H), 1.91-1.97 (m, 3H), 1.66-1.78 (m, 2H), 1.52-1.61 (m, 1H), 1.32-1.44 (m, 1H). MS (EI) for C₂₂H₂₃F₃IN₃O₃: 560 (M-H).

Example 3(ff)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,2-dimethylpropyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.45 (dd, 1H), 7.33-7.37 (m, 1H), 7.26-7.31 (m, 1H), 7.01-7.08 (m, 1H), 6.59-6.64 (m, 1H), 4.14-4.22 (m, 1H), 3.98-4.06 (m, 2H), 3.84-3.90 (m, 1H), 2.86-3.20 (m, 2H), 2.65 (br s, 1H), 1.92 (s, 2H), 1.76-1.86 (m, 1H), 1.06 (d, 3H), 0.91 (dd, 6H). MS (EI) for C₂₂H₂₅F₃, N₃O₂: 546 (M-H).

Example 3(gg)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-methyl-2-(methyloxy)ethyl]amino}methyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.55 (dd, 1H), 7.33-7.36 (m, 1H), 7.26-7.31 (m, 1H), 7.01-7.09 (m, 1H), 6.59-6.65 (m, 1H), 4.14-4.22 (m, 1H), 3.96-4.06 (m, 2H), 3.85-3.92 (m, 1H), 3.40-3.48 (m, 1H), 3.34 (s, 3H), 2.90-3.15 (m, 3H), 1.94 (s, 3H), 1.11 (d, 3H). MS (EI) for C₂₁H₂₃F₃IN₃O₃: 548 (M-H).

Example 3(hh)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-ethylpropyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.45 (dd, 1H), 7.33-7.36 (m, 1H), 7.26-7.31 (m, 1H), 7.01-7.09 (m, 1H), 6.58-6.65 (m, 1H), 4.15-4.20 (m, 1H), 3.99-4.06 (m, 2H), 3.86-3.91 (m, 1H), 2.94 (s, 2H), 2.55-2.63 (m, 1H), 1.92 (s, 2H), 1.48-1.58 (m, 4H), 0.92 (t, 6H). MS (EI) for C₂₂H₂₅F₃IN₃O₂: 546 (M-H).

Example 3(ii)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-1-ylmethyl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.67 (br s, 1H), 7.48 (m, 1H), 7.36 (m, 1H), 6.91 (br s, 1H), 6.63 (m, 1H), 4.25 (s, 2H), 4.22 (m, 1H), 4.02 (m, 2H), 3.82 (m, 1H). MS (EI) for C₂₀H₁₆F₃IN₄O₂: 529 (MH⁺).

Example 3(jj)

3-{[(cyclopropylmethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.47 (m, 1H), 7.36 (m, 1H), 7.31 (m, 1H), 7.05 (m, 1H), 6.62 (m, 1H), 4.30 (m, 1H), 4.24 (m, 2H), 3.99 (m, 1H), 3.66 (m, 2H), 2.91 (d, 2H), 1.08 (m, 1H), 0.71 (m, 2H), 0.40 (m, 2H). MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Example 3(kk)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(phenylmethyl)amino]methyl}azetidin-3-ol hydrochloride: ¹H NMR (400 MHz, CD₃OD): 7.47 (m, 5H), 7.43 (m, 1H), 7.35 (m, 1H), 7.27 (m, 1H), 7.04 (m, 1H), 6.61 (m, 1H), 4.24 (m, 3H), 4.08 (m, 2H), 3.96 (m, 1H). MS (EI) for C₂₄H₂₁F₃IN₃O₂: 568 (MH⁺).

Example 3(mm)

3-[(butylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1H), 7.57 (dd, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.67 (dt, 1H), 4.04 (d, 1H), 3.88 (q, 2H), 3.69 (d, 1H), 2.59 (s, 2H), 1.90 (s, 2H), 1.22-1.33 (m, 4H), 0.84 (t, 3H); MS (EI) for C₂₁H₂₃F₃IN₃O₂: 534 (MH⁺).

Example 3(nn)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-ethylpyrrolidin-2-yl)methyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.59 (s, 1H), 7.57 (dd, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.02 (t, 1H), 3.89 (q, 2H), 3.69 (d, 1H), 2.98 (s, 1H), 2.67-2.76 (m, 1H), 2.62 (s, 1H), 2.39-2.45 (m, 1H), 2.29 (s, 1H), 1.97-2.13 (m, 2H), 1.69 (s, 1H), 1.54 (s, 3H), 0.97 (t, 3H); MS (EI) for C₂₄H₂₈F₃IN₄O₂: 589 (MH⁺).

Example 3(oo)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyethyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.57 (s, 1H), 7.57 (dd, 1H), 7.37 (d, 1H), 7.32 (t, 1H), 7.18 (q, 1H), 6.68 (dt, 1H), 4.06 (d, 1H), 3.87 (d, 2H), 3.70 (d, 1H), 3.42 (t, 2H), 2.65 (s, 2H), 2.56 (dt, 2H), 1.91 (s, 2H); MS (EI) for C₁₉H₁₉F₃IN₃O₃: 522 (MH⁺).

Example 3(pp)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(dimethylamino)ethyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (dd, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.02 (d, 1H), 3.87 (t, 2H), 3.70 (d, 1H), 2.62 (s, 1H), 2.54 (t, 1H), 2.23 (t, 1H), 2.09 (s, 4H), 7.85 (s, 6H); MS (EI) for C₂₁H₂₄F₃IN₄O₂: 549 (MH⁺).

Example 3(qq)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (dt, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.04 (d, 1H), 3.89 (d, 2H), 3.79 (d, 1H), 2.88-2.92 (m, 1H), 2.61 (s, 2H), 2.15 (s, 3H), 1.93-2.04 (m, 2H), 1.75-1.83 (m, 3H), 1.54-1.70 (m, 3H), 1.20-1.37 (m, 2H); MS (EI) for C₂₄H₂₈F₃IN₄O₂: 589 (MH⁺).

Example 3(rr)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (dd, 1H), 7.37 (d, 1H), 7.31 (t, 1H), 7.14 (q, 1H), 6.68 (dt, 1H), 5.75 (s, 1H), 4.03 (t, 1H), 3.87 (t, 2H), 3.76 (q, 1H), 3.68 (q, 2H), 3.54-3.58 (m, 1H), 2.63 (s, 2H), 1.91 (s, 2H), 1.71-1.87 (m, 3H), 1.40-1.48 (m, 1H); MS (EI) for C₂₂H₂₃F₃IN₃O₃: 562 (MH⁺).

Example 3(ss)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-pyrrolidin-1-ylpropyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (dd, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.04 (d, 1H), 3.89 (d, 2H), 3.69 (d, 1H), 2.60 (s, 1H), 2.34-2.37 (m, 4H), 1.86 (s, 8H), 1.64 (s, 2H), 1.46-1.53 (m, 1H); MS (EI) for C₂₄H₂₈F₃IN₄O₂: 589 (MH⁺).

Example 3(tt)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(methyloxy)ethyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): ¹H NMR (400 MHz, d₆-DMSO): 8.57 (s, 1H), 7.57 (dd, 1H), 7.37 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.03 (d, 1H), 3.86 (d, 2H), 3.70 (d, 1H), 3.21 (s, 3H), 2.63 (s, 4H), 1.88 (s, 2H); MS (EI) for C₂₀H₂₁F₃IN₃O₃: 536 (MH⁺).

Example 3(uu)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methylpiperidin-4-yl)methyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (d, 1H), 7.37 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (t, 1H), 4.03 (d, 1H), 3.89 (t, 2H), 3.69 (d, 1H), 2.68 (d, 2H), 2.57 (s, 1H), 2.34 (d, 2H), 1.88 (s, 4H), 1.73 (t, 2H), 1.57 (d, 2H), 1.23 (s, 1H), 1.05 (q, 2H); MS (EI) for C₂₄H₂₈F₃IN₄O₃: 589 (MH⁺).

Example 3(vv)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[4-(dimethylamino)butyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 7.57 (dd, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.18 (q, 1H), 6.68 (dt, 1H), 4.03 (t, 2H), 3.88 (t, 2H), 3.70 (d, 1H), 3.08 (s, 1H), 2.60 (s, 1H), 2.44-2.47 (m, 2H), 2.28-2.33 (m, 1H), 2.07-2.16 (m, 6H), 1.29-1.35 (m, 4H); MS (EI) for C₂₃H₂₈F₃IN₄O₂: 577 (MH⁺).

Example 3(ww)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-furan-2-ylethyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (d, 1H), 7.49 (s, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (t, 1H), 6.33 (s, 1H), 6.08 (s, 1H), 5.72 (s, 1H), 4.04 (d, 1H), 3.87 (d, 2H), 3.70 (d, 1H), 2.74 (d, 2H), 2.69 (d, 2H), 2.64 (s, 2H); MS (EI) for C₂₃H₂₁F₃IN₃O₃: 572 (MH⁺).

Example 3(xx)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-ethylbutyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.56 (dd, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.67 (dt, 1H), 4.03 (d, 1H), 3.90 (d, 2H), 3.69 (d, 1H), 2.58 (s, 2H), 2.37 (d, 2H), 1.17-1.27 (m, 5H), 0.78 (t, 6H); MS (EI) for C₂₃H₂₇F₃IN₃O₂: 562 (MH⁺).

Example 3(yy)

1,1-dimethylethyl [3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)propyl]carbamate: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (d, 1H), 7.30-7.38 (m, 3H), 7.17 (q, 1H), 6.82 (t, 1H), 6.68 (dt, 1H), 4.07 (d, 1H), 3.89 (d, 2H), 3.70 (d, 1H), 3.36 (s, 2H), 2.93 (q, 2H), 2.61 (s, 2H), 1.46 (t, 2H), 1.36 (s, 9H); MS (EI) for C₂₅H₃₀F₃IN₄O₄: 635 (MH⁺).

Example 3(zz)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(pyrrolidin-2-ylmethyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.53 (s, 1H), 7.58 (dd, 1H), 7.37 (d, 1H), 7.33 (d, 1H), 7.18 (q, 1H), 6.67 (dt, 1H), 6.25 (s, 1H), 4.07 (d, 1H), 3.96 (q, 2H), 3.78 (s, 3H), 3.34 (s, 6H), 1.73 (s, 1H), 1.35-1.39 (m, 1H); MS (EI) for C₂₂H₂₄F₃IN₄O₂: 561 (MH⁺).

Example 3(aaa)

1,1-dimethylethyl 4-[({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)methyl]piperidine-1-carboxylate: ¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1H), 7.56 (dd, 1H), 7.36 (d, 1H), 7.30 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.03 (d, 1H), 3.88 (t, 4H), 3.69 (d, 1H), 2.58 (s, 2H), 2.35 (d, 2H), 1.60 (d, 2H), 1.47 (s, 1H), 1.39 (s, 10H), 0.90 (q, 2H); MS (EI) for C₂₈H₃₄F₃IN₄O₄: 675 (MH⁺).

Example 3(bbb)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(2-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1H), 7.54 (dd, 1H), 7.35 (d, 1H), 7.30 (t, 1H), 7.17 (q, 1H), 7.05 (t, 2H), 6.64-6.72 (m, 3H), 4.07 (d, 1H), 3.90 (t, 2H), 3.78 (s, 2H), 3.72 (d, 1H), 2.65 (s, 2H); MS (EI) for C₂₄H₂₁F₃IN₃O₃: 584 (MH⁺).

Example 3(ccc)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(3-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.56 (d, 1H), 7.35 (d, 1H), 7.29 (t, 1H), 7.16 (q, 1H), 7.06 (t, 1H), 6.64-6.72 (m, 3H), 6.60 (dd, 1H), 4.07 (d, 1H), 3.88 (t, 2H), 3.69 (d, 1H), 3.60 (s, 2H), 2.58 (d, 2H); MS (EI) for C₂₄H₂₁F₃IN₃O₃: 584 (MH⁺).

Example 3(ddd)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(4-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.57 (s, 1H), 7.55 (dd, 1H), 7.35 (d, 1H), 7.27 (t, 1H), 7.16 (q, 1H), 7.06 (d, 2H), 6.64-6.70 (m, 3H), 4.04 (d, 1H), 3.85 (t, 2H), 3.68 (d, 1H), 3.55 (s, 2H), 2.56 (d, 2H); MS (EI) for C₂₄H₂₁F₃IN₃O₃: 584 (MH⁺).

Example 3(eee)

3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)-5-(hydroxymethyl)cyclopentane-1,2-diol: ¹H NMR (400 MHz, d₆-DMSO): 8.60 (broad s, 1H), 7.57 (dd, 1H), 7.37 (d, 1H), 7.32 (t, 1H), 7.16 (q, 1H), 6.68 (t, 1H), 4.06 (q, 2H), 3.86 (t, 3H), 3.72 (dd, 1H), 3.60 (t, 1H), 3.36-3.43 (m, 2H), 3.30 (dd, 1H), 2.80 (q, 1H), 2.62-2.72 (m, 2H), 1.88-1.95 (m, 1H), 0.82-0.90 (m, 1H); MS (EI) for C₂₃H₂₅F₃IN₃O₅: 608 (MH⁺).

Example 3(fff)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(piperidin-4-ylmethyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.59 (broad s, 1H), 7.57 (dd, 1H), 7.37 (d, 1H), 7.30 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.03 (d, 1H), 3.87 (d, 2H), 3.69 (d, 1H), 3.01 (d, 2H), 2.59 (s, 2H), 2.43-2.56 (m, 1H), 2.35 (d, 2H), 1.65 (d, 2H), 1.47 (s, 1H), 1.07 (q, 2H); MS (EI) for C₂₃H₂₆F₃IN₄O₂: 575 (MH⁺).

Example 3(ggg)

3-{[(3-aminopropyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 7.57 (dd, 1H), 7.37 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.05 (d, 1H), 3.88 (d, 2H), 3.69 (d, 1H), 2.61 (t, 3H), 2.53-2.56 (m, 1H), 1.49 (t, 1.49); MS (EI) for C₂₃H₂₆F₃IN₄O₂: 535 (MH⁺).

Example 3(hhh)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[({[2-(4-methylpiperazin-1-yl)phenyl]methyl}amino)methyl]azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.59 (broad s, 1H), 7.55 (dd, 1H), 7.34 (t, 2H), 7.28 (d, 1H), 7.13-7.20 (m, 1H), 7.05 (d, 1H), 6.99 (t, 1H), 6.66 (dt, 1H), 4.03 (d, 1H), 3.90 (t, 2H), 3.71 (d, 3H), 2.83 (s, 5H), 2.60 (s, 2H), 2.42 (s, 3H), 2.20 (s, 3H); MS (EI) for C₂₉H₃₁F₃IN₅O₂: 666 (MH⁺).

Example 3(iii)

3-[(1H-benzimidazol-2-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.04 (s, 2H), 7.28-7.35 (m, 2H), 7.23-7.26 (m, 2H), 7.09-7.12 (m, 2H), 6.80 (q, 1H), 6.57-6.63 (m, 1H), 5.28 (broad s, 2H), 4.38 (s, 3H), 4.25 (s, 1H), 4.21 (d, 2H); MS (EI) for C₂₄H₁₉F₃IN₅O₂: 594 (MH⁺).

Example 3(jjj)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1H-imidazol-2-ylamino)methyl]azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 12.12 (s, 1H), 8.68 (s, 1H), 7.57-7.61 (m, 3H), 7.36-7.41 (m, 2H), 7.19 (q, 1H), 6.99 (s, 1H), 6.91 (s, 1H), 6.71 (dt, 1H), 6.45 (s, 1H), 4.28 (d, 1H), 4.06 (d, 1H), 4.03 (d, 1H), 3.82 (d, 2H); MS (EI) for C₂₄H₁₇F₃IN₅O₂: 544 (MH⁺).

Example 3(kkk)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{2-[(2,2,3,3,3-pentafluoropropyl)amino]ethyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (br s, 1H), 7.56 (dd, 1H), 7.37 (dd, 1H), 7.34-7.28 (m, 1H), 7.22-7.13 (m, 1H), 6.68 (ddd, 1H), 5.82 (br s, 1H), 4.06 (d, 1H), 3.91 (t, 2H), 3.70 (d, 1H), 3.40-3.25 (m, 2H), 2.76 (d, 2H), 2.40-2.31 (m, 1H); MS (EI) for C₂₀H₁₆F₈IN₃O₂: 610 (MH⁺).

Example 3(mmm)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{2-[(3,3,3-trifluoropropyl)amino]ethyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.58 (br s, 1H), 7.57 (dd, 1H), 7.37 (dd, 1H), 7.34-7.28 (m, 1H), 7.22-7.13 (m, 1H), 6.68 (ddd, 1H), 5.76 (br s, 1H), 4.05 (d, 1H), 3.88 (d, 2H), 3.70 (d, 1H), 2.71 (t, 2H), 2.63 (s, 2H), 2.41-2.26 (m, 2H); MS (EI) for C₂₀H₁₈F₆IN₃O₂: 574 (MH⁺).

Example 3(nnn)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2,3-dihydro-1H-inden-1-ylamino)methyl]azetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 8.61-8.56 (m, 1H), 7.55 (d, 1H), 7.37-7.07 (m, 8H), 6.71-6.64 (m, 1H), 4.16-4.05 (m, 2H), 3.98-3.85 (m, 2H), 3.72-3.68 (m, 1H), 2.90-2.82 (m, 1H), 2.74-2.64 (m, 2H), 1.91 (s, 3H), 1.73-1.63 (m, 1H); MS (EI) for C₂₆H₂₃F₃IN₃O₂: 594 (MH⁺).

Example 3(ooo)

3-[(cyclooctylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.55 (d, 1H), 7.20-7.14 (m, 2H), 6.70-6.66 (m, 1H), 4.03-3.98 (m, 1H), 3.92-3.86 (m, 2H), 3.72-3.67 (m, 1H), 2.60 (s, 2H), 1.90 (s, 3H), 1.64-1.22 (m, 15H); MS (EI) for C₂₅H₂₉F₃IN₃O₂: 588 (MH⁺).

Example 3(ppp)

3-[(cycloheptylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 8.55 (s, 1H), 7.55 (d, 1H), 7.36-7.28 (m, 2H), 7.21-7.14 (m, 1H), 6.70-6.66 (m, 1H), 4.04-4.00 (m, 1H), 3.92-3.85 (m, 2H), 3.71-3.66 (m, 1H), 2.60 (s, 2H), 1.90 (s, 3H), 1.70-1.13 (m, 13H); MS (EI) for C₂₄H₂₇F₃IN₃O₂: 574 (MH⁺).

Example 3(qqq)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-pyridin-3-ylethyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 8.58 (s, 1H), 8.42-8.37 (m, 2H), 7.62-7.54 (m, 2H), 7.38-7.27 (m, 3H), 7.21-7.14 (m, 1H), 6.71-6.66 (m, 1H), 4.06-4.02 (m, 1H), 3.90-3.86 (m, 2H), 3.72-3.68 (m, 1H), 2.80-2.64 (m, 6H), 1.90 (s, 3H); MS (EI) for C₂₄H₂₂F₃IN₄O₂: 583 (MH⁺).

Example 3(rrr)

N-cyclohexyl-N2-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-2-methylalaninamide acetate salt: ¹H NMR (400 MHz, DMSO): 8.66 (br s 1H), 8.55 (s, 1H), 7.93-7.90 (m, 1H), 7.58 (d, 1H), 7.40-7.31 (m, 2H), 7.24-7.17 (m, 1H), 6.71-6.66 (m, 1H), 6.60 (br s, 1H), 4.28-4.23 (m, 1H), 4.14-4.02 (m, 2H), 3.89-3.83 (m, 1H), 3.12 (br s, 2H), 1.90 (s, 3H), 1.74-1.42 (m, 1H), 1.31-1.02 (m, 6H); MS (EI) for C₂₇H₃₂F₃IN₄O₃: 645 (MH⁺).

Example 3(sss)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.56 (d, 1H), 7.38-7.27 (m, 2H), 7.20-7.14 (m, 1H), 6.71-6.66 (m, 1H), 4.05-4.01 (m, 1H), 3.91-3.78 (m, 4H), 3.71-3.67 (m, 1H), 3.25-3.18 (m, 2H), 2.60 (s, 2H), 2.36 (d, 2H), 1.90 (s, 3H), 1.57-1.50 (m, 3H), 1.13-1.02 (m, 2H); MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(ttt)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(dimethylamino)-1-methylethyl]amino}methyl)azetidin-3-ol trifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 8.59-8.54 (m, 1H), 7.56 (d, 1H), 7.38-7.28 (m, 2H), 7.21-7.13 (m, 1H), 6.71-6.63 (m, 1H), 4.04-3.95 (m, 1H), 3.88-3.78 (m, 2H), 3.73-3.68 (m, 1H), 2.70-2.50 (m, 3H), 2.08 (s, 6H), 1.88 (s, 2H), 0.85-0.82 (m, 3H); MS (EI) for C₂₂H₂₆F₃IN₄O₂: 563 (MH⁺).

Example 3(uuu)

N-cyclopropyl-1-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)cyclopentanecarboxamide trifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 8.80 (br s, 1H), 8.58 (s, 1H), 8.04 (s, 1H), 7.59 (d, 1H), 7.40-7.31 (m, 2H), 7.25-7.16 (m, 1H), 6.74-6.58 (m, 2H), 4.26-3.82 (m, 4H), 3.10 (br s, 2H), 2.69-2.64 (m, 1H), 2.11-1.88 (m, 4H), 1.82-1.61 (m, 4H), 0.67-0.62 (m, 2H), 0.52-0.48 (m, 2H); MS (EI) for C₂₆H₂₈F₃IN₄O₃: 629 (MH⁺).

Example 3(vvv)

N2-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-N-ethyl-2-methylalaninamide acetate salt: ¹H NMR (400 MHz, DMSO): 8.60 (s, 1H), 7.60-7.72 (m, 1H), 7.56 (d, 1H), 7.38-7.30 (m, 2H), 7.22-7.14 (m, 1H), 6.69-6.63 (m, 1H), 4.07-4.04 (m, 1H), 3.95-3.90 (m, 2H), 3.72-3.68 (m, 1H), 3.05-3.01 (m, 2H), 2.47 (br s, 2H), 1.90 (s, 3H), 1.09 (s, 6H), 0.94 (t, 3H); MS (EI) for C₂₃H₂₆F₃IN₄O₃: 591 (MH⁺).

Example 3(www)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2-methylhydrazino)methyl]azetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 8.54 (s, 1H), 7.57 (d, 1H), 7.38-7.30 (m, 2H), 7.19-7.12 (m, 1H), 6.69-6.63 (m, 1H), 4.04-4.01 (m, 1H), 3.92-3.84 (m, 2H), 3.68-3.63 (m, 1H), 2.55 (s, 2H), 2.39 (s, 3H), 1.90 (s, 3H); MS (EI) for C₁₈H₁₈F₃IN₄O₂: 507 (MH⁺).

Example 3(xxx)

3-[(azetidin-3-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 7.57 (d, 1H), 7.39-7.30 (m, 2H), 7.20-7.13 (m, 1H), 6.70-6.65 (m, 1H), 4.10-4.04 (m, 1H), 3.90-3.83 (m, 2H), 3.78-3.67 (m, 3H), 3.61-3.53 (m, 1H), 3.48-3.42 (m, 2H), 2.61-2.54 (m, 2H), 1.90 (s, 3H); MS (EI) for C₂₀H₂₀F₃IN₄O₂: 533 (MH⁺).

Example 3(yyy)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1,3-thiazol-2-ylamino)methyl]azetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 8.60 (s, 1H), 7.57 (d, 1H), 7.38-7.28 (m, 2H), 7.20-7.13 (m, 1H), 6.75 (d, 1H), 6.70-6.64 (m, 1H), 5.93 (d, 1H), 4.26-4.22 (m, 1H), 4.11-4.08 (m, 1H), 4.00-3.88 (m, 3H), 3.74-3.70 (m, 1H), 1.90 (s, 3H); MS (EI) for C₂₀H₁₆F₃IN₄O₂S: 561 (MH⁺).

Example 3(zzz)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(methyloxy)phenyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, DMSO): 8.57 (s, 1H), 7.56 (d, 1H), 7.38-7.30 (m, 2H), 7.20-7.12 (m, 1H), 6.95-6.91 (m, 1H), 6.70-6.66 (m, 1H), 6.21-6.17 (m, 2H), 6.14-6.10 (m, 1H), 5.94 (s, 1H), 5.49-5.44 (m, 1H), 4.14-4.10 (m, 1H), 3.98-3.93 (m, 2H), 3.78-3.75 (m, 1H), 3.65 (s, 3H), 3.21 (d, 2H); MS (EI) for C₂₄H₂₁F₃IN₃O₃: 584 (MH⁺).

Example 3(ab)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[4-(methyloxy)phenyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.58 (d, 1H), 7.39-7.30 (d, 2H), 7.20-7.13 (m, 1H), 6.71-6.66 (m, 3H), 6.55 (d, 2H), 5.93 (s, 1H), 5.00-4.95 (m, 1H), 4.14-4.08 (m, 1H), 3.98-3.92 (m, 2H), 3.79-3.74 (m, 1H), 3.63 (s, 3H), 3.13 (d, 2H); MS (EI) for C₂₄H₂₁F₃IN₃O₃: 584 (MH⁺).

Example 3(ac)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(ethyloxy)ethyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.24-4.16 (d, 1H), 4.08-3.98 (t, 2H), 3.92-3.85 (d, 1H), 3.60-3.55 (t, 2H), 3.54-3.47 (q, 2H), 3.01-2.96 (s, 2H), 2.94-2.89 (t, 2H), 1.20-1.15 (t, 3H); MS (EI) for C₂₁H₂₃F₃IN₃O₃: 550 (MH⁺).

Example 3(ad)

3-({[2,2-bis(methyloxy)ethyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.32 (d, 1H), 7.30-7.24 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.57 (t, 1H), 4.48-4.42 (t, 1H), 4.20-4.11 (d, 1H), 4.02-3.93 (t, 2H), 3.86-3.80 (d, 1H), 3.38-3.34 (s, 6H), 2.84-2.80 (s, 2H), 2.75-2.70 (d, 2H), 1.93-1.87 (s, 3H); MS (EI) for C₂₁H₂₃F₃IN₃O₄: 566 (MH⁺).

Example 3(ae)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-hydroxypropyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.38-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.09-7.00 (q, 1H), 6.66-6.58 (t, 1H), 4.31-4.23 (d, 1H), 4.16-4.05 (t, 2H), 3.99-3.89 (d, 1H), 3.70-3.64 (t, 2H), 3.26-3.22 (s, 2H), 3.11-3.04 (t, 2H), 1.93-1.89 (s, 3H), 1.89-1.82 (t, 3H); MS (EI) for C₂₀H₂₁F₃IN₃O₃: 536 (MH⁺).

Example 3(af)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-pyridin-4-ylethyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 8.36-8.32 (d, 2H), 7.38-7.33 (d, 1H), 7.26-7.14 (m, 3H), 7.00-6.91 (q, 1H), 4.12-4.04 (d, 1H), 3.96-3.88 (t, 2H), 3.80-3.73 (d, 2H), 2.92-2.74 (m, 6H), 1.87-1.84 (s, 3H); MS (EI) for C₂₄H₂₂F₃IN₄O₂: 583 (MH⁺).

Example 3(ag)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-(phenylmethyl)pyrrolidin-3-yl]amino}methyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.47-7.24 (m, 8H), 7.08-7.00 (q, 1H), 6.64-6.57 (t, 1H), 4.19-4.11 (d, 1H), 4.05-3.81 (m, 5H), 3.52-3.44 (m, 1H), 3.09-2.99 (m, 2H), 2.91-2.76 (m, 3H), 1.93-1.91 (s, 3H), 1.82-1.71 (m, 1H); MS (EI) for C₂₈H₂₈F₃IN₄O₂: 637 (MH⁺).

Example 3(ah)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(2-thienyl)ethyl]amino}methyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.47-7.42 (d, 1H), 7.36-7.31 (d, 1H), 7.30-7.24 (m, 1H), 7.21-7.17 (d, 1H), 7.08-7.00 (q, 1H), 6.93-6.89 (t, 1H), 6.86-6.83 (d, 1H), 6.64-6.57 (t, 1H), 4.18-4.11 (d, 1H), 4.01-3.93 (t, 2H), 3.85-3.78 (d, 1H), 3.04-2.97 (t, 2H), 2.92-2.87 (t, 2H), 2.82-2.78 (s, 2H), 1.92-1.87 (s, 3H); MS (EI) for C₂₃H₂₁F₃IN₃O₂S: 588 (MH⁺).

Example 3(ai)

3-[({2-[bis(1-methylethyl)amino]ethyl}amino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.18-4.13 (d, 1H), 4.06-3.98 (t, 2H), 3.88-3.82 (d, 2H), 3.57-3.47 (q, 2H), 3.05-2.99 (t, 2H), 2.92-2.85 (t, 4H), 1.92-1.88 (s, 3H), 1.28-1.22 (d, 12H); MS (EI) for C₂₅H₃₂F₃IN₄O₂: 605 (MH⁺).

Example 3(aj)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(phenyloxy)ethyl]amino}methyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.36-7.31 (d, 1H), 7.26-7.22 (d, 1H), 7.20-7.13 (m, 3H), 6.97-6.89 (t, 1H), 6.86-6.80 (m, 3H), 6.54-6.47 (t, 1H), 4.13-4.07 (d, 1H), 4.01-3.96 (t, 2H), 3.79-3.74 (d, 1H), 2.97-2.91 (t, 2H), 2.84-2.79 (s, 2H), 1.84-1.81 (s, 3H); MS (EI) for C₂₅H₂₃F₃IN₃O₃: 598 (MH⁺).

Example 3(ak)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxypropyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.27-4.19 (d, 1H), 4.10-4.00 (m, 2H), 3.15-3.00 (t, 2H), 3.57-3.47 (q, 2H), 3.15-3.00 (t, 2H), 2.87-2.81 (d, 1H), 2.72-2.64 (t, 1H), 1.94-1.91 (s, 3H), 1.19-1.15 (d, 3H); MS (EI) for C₂₀H₂₁F₃IN₃O₃: 536 (MH⁺).

Example 3(am)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[({2-[(1-methylethyl)oxy]ethyl}amino)methyl]azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.21-4.13 (d, 1H), 4.04-3.95 (t, 2H), 3.88-3.82 (d, 1H), 3.64-3.51 (m, 3H), 2.89-2.84 (s, 2H), 2.83-2.77 (t, 2H), 1.91-1.89 (s, 3H), 1.15-1.12 (d, 6H); MS (EI) for C₂₂H₂₅F₃IN₃O₃: 564 (MH⁺).

Example 3(an)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-ethylpiperidin-3-yl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.17-4.10 (d, 1H), 4.04-3.95 (t, 2H), 3.88-3.82 (d, 1H), 3.24-3.06 (m, 2H), 2.95-2.75 (m, 6H), 2.76-2.46 (m, 2H), 1.93-1.90 (s, 3H), 1.74-1.62 (m, 1H), 1.44-1.31 (m, 1H), 1.28-1.20 (t, 3H); MS (EI) for C₂₄H₂₈F₃IN₄O₂: 589 (MH⁺).

Example 3(ao)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]amino}methyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.20-4.13 (d, 1H), 4.00-3.90 (t, 2H), 3.83-3.75 (d, 1H), 2.84-2.78 (s, 2H), 2.53-2.48 (s, 2H), 1.93-1.87 (s, 3H); MS (EI) for C₂₁H₁₉F₃IN₅O₃: 574 (MH⁺).

Example 3(ap)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylbutyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.38-7.33 (d, 1H), 7.32-7.27 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.25-4.19 (d, 1H), 4.12-4.02 (t, 2H), 3.96-3.90 (d, 1H), 3.16-2.96 (m, 3H), 1.91-1.89 (s, 3H), 1.68-1.57 (m, 1H), 1.49-1.29 (m, 3H), 1.23-1.18 (d, 3H), 0.99-0.92 (t, 3H); MS (EI) for C₂₂H₂₅F₃IN₃O₂: 548 (MH⁺).

Example 3(aq)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylpropyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.27-4.20 (d, 1H), 4.14-4.03 (t, 2H), 3.98-3.92 (d, 1H), 3.20-3.16 (s, 2H), 3.07-2.97 (m, 1H), 1.91-1.89 (s, 3H), 1.80-1.70 (m, 1H), 1.54-1.41 (m, 1H), 1.26-1.22 (d, 3H), 1.00-0.94 (t, 3H); MS (EI) for C₂₁H₂₃F₃IN₃O₂: 534 (MH⁺).

Example 3(ar)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-methylbutyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.26-4.19 (d, 1H), 4.10-4.01 (t, 2H), 3.94-3.87 (d, 1H), 3.05-2.99 (s, 2H), 2.77-2.70 (m, 1H), 2.61-2.54 (m, 1H), 1.91-1.89 (s, 3H), 1.73-1.61 (m, 1H), 1.49-1.39 (m, 1H), 1.24-1.12 (m, 1H), 0.94-0.84 (m, 6H); MS (EI) for C₂₂H₂₅F₃IN₃O₂: 548 (MH⁺).

Example 3(as)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(pentylamino)methyl]azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.29-4.23 (d, 1H), 4.15-4.05 (t, 2H), 3.98-3.90 (d, 1H), 3.21-3.18 (s, 2H), 2.93-2.86 (m, 2H), 1.91-1.89 (s, 3H), 1.70-1.60 (m, 2H), 1.42-1.29 (m, 4H), 0.97-0.90 (t, 3H); MS (EI) for C₂₂H₂₅F₃IN₃O₂: 548 (MH⁺).

Example 3(at)

3-[(cyclohexylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.38-7.34 (d, 1H), 7.33-7.27 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.25-4.19 (d, 1H), 4.14-4.03 (t, 2H), 3.98-3.90 (d, 1H), 3.21-3.18 (s, 2H), 2.93-2.86 (m, 1H), 2.07-2.00 (d, 2H), 1.92-1.90 (s, 3H), 1.89-1.82 (d, 2H), 1.73-1.66 (d, 1H), 1.42-1.14 (m, 5H); MS (EI) for C₂₃H₂₅F₃IN₃O₂: 560 (MH⁺).

Example 3(au)

3-[(azepan-3-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.19-4.13 (d, 1H), 4.05-3.95 (t, 2H), 3.90-3.81 (d, 1H), 3.37-3.34 (s, 2H), 3.22-3.03 (m, 2H), 2.91-2.64 (m, 3H), 1.93-1.89 (s, 3H), 1.88-1.52 (m, 6H); MS (EI) for C₂₃H₂₆F₃IN₄O₂: 575 (MH⁺).

Example 3(av)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(2,3-dihydro-1H-indol-3-yl)ethyl]amino}methyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.58-7.54 (d, 1H), 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.14-6.99 (m, 4H), 6.65-6.58 (t, 1H), 4.25-4.19 (d, 1H), 4.10-4.02 (t, 2H), 3.95-3.88 (d, 1H), 3.23-3.03 (m, 9H), 1.94-1.92 (s, 3H); MS (EI) for C₂₇H₂₆F₃IN₄O₂: 623 (MH⁺).

Example 3(aw)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1,3,5-triazin-2-ylamino)methyl]azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 8.48-8.46 (s, 1H), 8.36-8.34 (s, 1H), 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.28-7.22 (m, 1H), 7.06-6.98 (q, 1H), 6.65-6.58 (t, 1H), 4.24-4.18 (d, 1H), 4.10-3.96 (t, 2H), 3.84-3.78 (d, 1H), 3.69-3.67 (s, 2H), 1.99-1.97 (s, 3H); MS (EI) for C₂₀H₁₆F₃IN₆O₂: 557 (MH⁺).

Example 3(ax)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(4-hydroxycyclohexyl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.22-4.15 (d, 1H), 4.08-3.99 (t, 2H), 3.93-3.87 (d, 1H), 3.56-3.47 (m, 1H), 3.05-3.02 (s, 2H), 2.76-2.68 (m, 1H), 2.03-1.96 (m, 4H), 1.93-1.89 (s, 3H), 1.35-1.23 (m, 4H); MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(ay)

3-[(cyclopent-3-en-1-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 5.70-5.65 (s, 2H), 4.20-4.14 (d, 1H), 4.03-3.95 (t, 2H), 3.90-3.81 (d, 1H), 3.58-3.50 (m, 1H), 2.90-2.86 (s, 2H), 2.68-2.58 (m, 2H), 2.26-2.16 (m, 2H), 1.93-1.89 (s, 3H); MS (EI) for C₂₂H₂₁F₃IN₃O₂: 544 (MH⁺).

Example 3(az)

N-[4-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)phenyl]acetamide acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.27-7.20 (m, 3H), 7.09-7.01 (q, 1H), 6.65-6.55 (m, 3H), 4.22-4.16 (d, 1H), 4.08-3.98 (t, 2H), 3.88-3.82 (d, 1H), 3.28-3.24 (s, 2H), 2.08-2.05 (s, 3H), 2.91-2.64 (m, 3H), 1.93-1.89 (s, 3H); MS (EI) for C₂₅H₂₂F₃IN₄O₃: 611 (MH⁺).

Example 3(ba)

N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)phenyl]acetamide acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.27-7.20 (m, 1H), 7.04-6.96 (m, 3H), 6.72-6.68 (d, 1H), 6.65-6.58 (t, 1H), 6.40-6.35 (d, 1H), 4.24-4.18 (d, 1H), 4.08-3.98 (t, 2H), 3.87-3.81 (d, 1H), 3.28-3.25 (s, 2H), 2.10-2.07 (s, 3H), 1.97-1.95 (s, 3H); MS (EI) for C₂₅H₂₂F₃IN₄O₃: 611 (MH⁺).

Example 3(bc)

(1R,2S)-4-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)cyclopentane-1,2-diol acetate salt: ¹H NMR (400 MHz, DMSO): 8.58-8.54 (s, 1H), 7.61-7.53 (d, 1H), 7.39-7.28 (m, 2H), 7.21-7.13 (m, 1H), 6.71-6.63 (t, 1H), 5.58-5.64 (s, 1H), 5.63-5.58 (s, 1H), 4.06-4.01 (d, 1H), 3.90-3.84 (t, 2H), 3.72-3.66 (d, 1H), 3.31-3.26 (m, 3H), 2.61-2.57 (s, 2H), 2.46-2.36 (m, 2H), 2.02-1.93 (dd, 2H), 1.91-1.88 (s, 3H); MS (EI) for C₂₂H₂₃F₃IN₃O₄: 578 (MH⁺).

Example 3(bd)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-(hydroxymethyl)cyclohexyl]amino}methyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.22-4.15 (d, 1H), 4.08-3.99 (t, 2H), 3.89-3.83 (d, 1H), 3.49-3.45 (s, 2H), 2.86-2.80 (s, 2H), 1.91-1.89 (s, 3H), 1.67-1.34 (m, 10H); MS (EI) for C₂₄H₂₇F₃IN₃O₃: 590 (MH⁺).

Example 3(be)

3-{[(3-chlorophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.08-6.98 (m, 2H), 6.65-6.55 (m, 3H), 6.53-6.44 (d, 1H), 4.22-4.15 (d, 1H), 4.06-3.98 (t, 2H), 3.88-3.82 (d, 1H), 3.27-3.24 (s, 2H), 1.91-1.89 (s, 3H); MS (EI) for C₂₃H₁₈ClF₃IN₃O₂: 588 (MH⁺).

Example 3(bf)

3-{[(4-chlorophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.45-7.40 (d, 1H), 7.35-7.30 (d, 1H), 7.28-7.22 (m, 1H), 7.06-6.97 (m, 3H), 6.62-6.54 (m, 3H), 6.53-6.44 (d, 1H), 4.22-4.15 (d, 1H), 4.06-3.98 (t, 2H), 3.88-3.82 (d, 1H), 3.26-3.22 (s, 2H), 1.96-1.94 (s, 3H); MS (EI) for C₂₃H₁₈ClF₃IN₃O₂: 588 (MH⁺).

Example 3(bg)

3-[(5-amino-3-methyl-1H-pyrazol-1-yl)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.38-7.33 (d, 1H), 7.28-7.24 (d, 1H), 7.21-7.15 (m, 1H), 6.98-6.90 (q, 1H), 6.56-6.49 (t, 1H), 5.16-5.14 (s, 1H), 4.36-4.30 (d, 1H), 4.22-4.16 (d, 1H), 3.99-3.97 (s, 1H), 3.95-3.90 (d, 1H), 3.77-3.71 (d, 1H), 1.96-1.92 (s, 3H), 1.85-1.82 (s, 3H); MS (EI) for C₂₁H₁₉F₃IN₅O₂: 558 (MH⁺).

Example 3(bh)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(5-methyl-1H-pyrazol-3-yl)amino]methyl}azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.38-7.33 (d, 1H), 7.28-7.24 (d, 1H), 7.21-7.15 (m, 1H), 6.98-6.90 (q, 1H), 6.56-6.49 (t, 1H), 5.22-5.19 (s, 1H), 4.15-4.08 (d, 1H), 4.02-3.88 (m, 2H), 3.75-3.68 (d, 1H), 3.20-3.18 (s, 2H), 2.07-2.05 (s, 3H), 1.85-1.82 (s, 3H); MS (EI) for C₂₁H₁₉F₃IN₅O₂: 558 (MH⁺).

Example 3(bi)

3-[(diethylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.54 (s, 1H), 7.58-7.55 (dd, 1H), 7.38-7.35 (dt, 1H), 7.33-7.31 (m, 1H), 7.22-7.15 (m, 1H), 6.69-6.64 (m, 1H), 5.56 (b, 1H), 4.06-4.04 (d, 1H), 3.90-3.88 (m, 2H), 3.72-3.69 (d, 1H), 2.51-2.49 (m, 6H), 0.86-0.83 (t, 6H); MS (EI) for C₂₁H₂₃F₃IN₃O₂: 534 (MH⁺).

Example 3(bj)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(dimethylamino)methyl]azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1H), 7.59-7.56 (dd, 1H), 7.38-7.36 (dt, 1H), 7.34-7.33 (m, 1H), 7.21-7.14 (m, 1H), 6.71-6.65 (m, 1H), 5.55 (b, 1H), 4.07-4.05 (d, 1H), 3.89-3.84 (t, 2H), 3.74-3.719 (d, 1H), 2.46 (m, 2H), 2.19 (br s, 6H); MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 3(bk)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxy-1,1-dimethylethyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.40 (s, 1H), 7.38 (dd, 1H), 7.33-7.30 (m, 1H), 7.12 (m, 1H), 6.85-6.79 (m, 1H), 6.63-6.57 (m, 1H), 4.22-4.11 (br m, 4H), 3.55 (s, 2H), 3.15 (s, 2H), 1.32 (s, 6H); MS (EI) for C₂₁H₂₃F₃IN₃O₃: 550 (MH⁺).

Example 3(bm)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(prop-2-en-1-ylamino)methyl]azetidin-3-ol): ¹H NMR (400 MHz, CDCl₃): 8.47 (s, 1H), 7.40 (dd, 1H), 7.34-7.31 (m, 1H), 7.12 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.59 (m, 1H), 6.64-6.59 (m, 1H), 5.88-5.78 (m, 1H), 5.00-5.12 (m, 2H), 4.13 (br m, 4H), 3.26 (d, 2H), 2.88 (d, 2H), 2.02 (s, 1H); MS (EI) for C₂₁H₁₉F₃IN₃O₂: 518 (MH⁺).

Example 3(bn)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(tetrahydro-2H-pyran-4-yl)ethyl]amino}methyl)azetidin-3-ol): ¹H NMR (400 MHz, CDCl₃): 8.45 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.26-4.04 (m, 4H), 3.95 (dd, 2H), 3.35 (t, 2H), 2.92 (d, 2H), 2.67 (m, 2H), 1.40-1.25 (m, 8H); MS (EI) for C₂₄H₂₇F₃IN₃O₃: 590 (MH⁺).

Example 3(bo)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethylprop-2-yn-1-yl)amino]methyl}azetidin-3-ol): ¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.39 (dd, 1H), 7.33-7.30 (m, 1H), 7.15-7.11 (m, 1H), 6.84-6.77 (m, 1H), 6.64-6.58 (m, 1H), 4.20 (br, 1H), 4.07 (br, 1H), 2.92 (s, 2H), 1.58 (m, 4H), 0.92 (dd, 6h); MS (EI) for C₂₂H₂₁F₃IN₃O₂: 572 (MH⁺).

Example 3(bp)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)azetidin-3-ol): ¹H NMR (400 MHz, CDCl₃): 8.44 (s, 1H), 7.33-7.14 (m, 3H), 7.00 (m, 1H), 6.67 (dd, 1H), 6.59 (s, 1H), 6.44 (m, 1H), 3.93 (d, 2H), 2.75 (m, 2H), 2.60 (m, 1H), 2.42 (m, 1H) 2.02 (AcOH; s, 3H), 1.86 (m, 4H); MS (EI) for C₂₂H₂₁F₃IN₅O₂: 572 (MH⁺).

Example 3(bq)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(ethyloxy)propyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H), 7.14-7.10 (m, 1H), 6.83-6.76 (m, 1H), 6.64-6.58 (m, 1H), 4.26-4.03 (br m, 4H), 3.53-3.44 (m, 4H), 2.92-2.73 (m, 4H), 1.72 (m, 2H) 1.18 (t, 3H); MS (EI) for C₂₂H₂₃F₃IN₃O₃: 564 (MH⁺).

Example 3(br)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3,3-dimethylbutyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.18 (br, 3H), 3.15 (s, 2H), 2.71 (m, 2H) 2.05 (AcOH; s, 3H), 1.43 (m, 2H), 0.90 (s, 9H); MS (EI) for C₂₃H₂₇F₃IN₃O₂: 562 (MH⁺).

Example 3(bs)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-methylbutyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.39 (dd, 1H), 7.34-7.30 (m, 1H), 7.14-7.11 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.59 (m, 1H), 4.27-3.61 (br m, 6H), 2.98 (m, 2H), 2.72 (t, 2H) 2.05 (AcOH; s, 3H), 1.61 (m, 1H), 1.43 (m, 2H), 0.90 (d, 6H); MS (EI) for C₂₂H₂₅F₃IN₃O₂: 547 (MH⁺).

Example 3(bt)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(dimethylamino)propyl]amino}methyl)azetidin-3-ol: MS (EI) for C₂₂H₂₆F₃IN₄O₂: 563 (MH⁺).

Example 3(bu)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(1H-imidazol-1-yl)propyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.53 (s, 1H), 7.40 (dd, 1H), 7.34-7.30 (m, 1H), 7.14-7.09 (m, 1H), 7.05 (s, 1H), 6.89 (s, 1H), 6.84-6.77 (m, 1H), 6.63-6.59 (m, 1H), 4.24-4.00 (br m, 6H), 2.84 (m, 2H), 2.61 (m, 2H), 1.94 (m, 2H); MS (EI) for C₂₃H₂₁F₃IN₅O₂: 586 (MH⁺).

Example 3(bv)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(methylthio)ethyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H), 7.14-7.11 (m, 1H), 6.83-6.77 (m, 1H), 6.63-6.59 (m, 1H), 4.26-4.03 (br m, 4H), 2.88 (s, 2H), 2.82 (t, 2H), 2.62 (t, 2H), 2.08 (s, 3H); MS (EI) for C₂₃H₂₁F₃IN₃O₂S: 552 (MH⁺).

Example 3(bw)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1,3,3-tetramethylbutyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.38 (dd, 1H), 7.34-7.30 (m, 1H), 7.14-7.11 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.59 (m, 1H), 4.25-4.01 (br m, 4H), 2.82 (s, 2H), 1.45 (s, 2H), 1.15 (s, 6H), 0.90 (s, 9H); MS (EI) for C₂₅H₃₁F₃IN₃O₂: 590 (MH⁺).

Example 3(bx)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethylpropyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.50 (s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7.15-7.11 (m, 1H), 6.83-6.77 (m, 1H), 6.65-6.59 (m, 1H), 4.27-4.01 (br m, 4H), 2.82 (s, 2H), 1.46 (s, 2H), 1.08 (s, 6H), 0.89 (s, 3H); MS (EI) for C₂₂H₂₁F₃IN₄O₃: 548 (MH⁺).

Example 3(by)

3-{[(3-amino-2-hydroxypropyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: MS (EI) for C₂₃H₂₂F₃IN₄O₃: 551 (MH⁺).

Example 3(bz)

1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}pyrrolidin-3-ol: (EI) for C₂₂H₂₁F₃IN₃O₃: 548 (MH⁺).

Example 3(ca)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({(2S)-2-[(methyloxy)methyl]pyrrolidin-1-yl}methyl)azetidin-3-ol: MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(cb)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyphenyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.41 (dd, 1H), 7.35-7.30 (m, 1H), 7.15-7.11 (m, 1H), 6.89-5.98 (m, 6H), 4.92 (s, 1H), 4.28-4.05 (br m, 4H), 3.44 (s, 2H); MS (EI) for C₂₃H₁₉F₃IN₃O₃: 570 (MH⁺).

Example 3(cd)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(4-hydroxyphenyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.78 (s, 1H), 7.40-7.05 (m, 4H), 6.72 (m, 1H), 6.62 (d, 1H), 6.50 (m, 1H), 6.42 (d, 1H) 4.04-3.98 (m, 4H), 3.18 (s, 2H); MS (EI) for C₂₃H₁₉F₃IN₃O₃: 570 (MH⁺).

Example 3(ce)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-hydroxyphenyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.52 (s, 1H), 8.22 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H), 7.14-7.11 (m, 1H), 6.85 (dd, 1H), 6.84-6.77 (m, 1H), 6.63-6.59 (m, 1H), 6.15 (d, 1H) 6.09-6.01 (m, 3H), 4.16-3.95 (br m, 4H), 3.22 (d, 2H) 2.15 (AcOH; s, 3H); MS (EI) for C₂₃H₁₉F₃IN₃O₃: 570 (MH⁺).

Example 3(cf)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(phenyloxy)methyl]azetidin-3-ol: MS (EI) for C₂₃H₁₈F₃IN₂O₃: 555 (MH⁺).

Example 3(cg)

3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)propane-1,2-diol: MS (EI) for C₂₀H₂₁F₃IN₃O₄: 552 (MH⁺).

Example 3(ch)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(phenylthio)methyl]azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.45-7.23 (m, 5H), 7.14-7.05 (m, 1H), 6.78 (dd, 1H), 6.60 (m, 1H), 4.14-3.92 (br m, 4H), 3.33 (s, 2H); MS (EI) for C₂₃H₁₈F₃IN₂O₂: 571 (MH⁺).

Example 3(ci)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(4-hydroxybutyl)amino]methyl}azetidin-3-ol): ¹H NMR (400 MHz, CDCl₃): 8.43 (s, 1H), 7.38 (dd, 1H), 7.34-7.30 (m, 1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.26-4.04 (m, 4H), 3.61 (m, 2H), 2.96 (s, 2H), 2.73 (s, 2H); MS (EI) for C₂₁H₂₃F₃IN₃O₃: 550 (MH⁺).

Example 3(cj)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyethyl)oxy]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.51 (s, 1H), 7.39 (dd, 1H), 7.35-7.31 (m, 1H), 7.14-7.11 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.59 (m, 1H), 4.21-4.05 (br m, 4H), 3.77 (m, 2H), 3.66 (m, 2H); MS (EI) for C₁₉H₁₈F₃IN₂O₄: 523 (MH⁺).

Example 3(ck)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1S,2S)-2-hydroxycyclohexyl]amino}methyl)azetidin-3-ol): MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(cm)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethyl-2-pyrrolidin-1-ylethyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.39 (dd, 1H), 7.34-7.29 (m, 1H), 7.14-7.11 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.59 (m, 1H), 4.25-4.07 (br m, 4H), 2.88 (d, 2H), 2.62 (m, 4H), 2.58 (m, 2H), 1.78 (m, 4H), 2.05 (AcOH; s, 3H); MS (EI) for C₂₅H₃₀F₃IN₄O₂: 603 (MH⁺).

Example 3(cn)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methyl-1H-imidazol-4-yl)methyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.50 (s, 1H), 7.41-7.11 (m, 3H), 7.12 (m, 1H), 6.85-6.79 (m, 2H), 4.12-3.98 (br m, 4H), 3.78 (s, 2H), 3.66 (s, 3H), 2.95 (s, 2H), 2.08 (AcOH; s, 4H), 2.05 (AcOH; s, 3H); MS (EI) for C₂₂H₂₁F₃IN₅O₂: 572 (MH⁺).

Example 3(co)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methyl-1H-imidazol-5-yl)methyl]amino}methyl)azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.45 (s, 1H), 7.47 (s, 1H), 7.39 (dd, 1H), 7.33-7.30 (m, 1H), 7.15-7.10 (m, 1H), 6.91 (s, 1H), 6.87-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.18-4.02 (m, 4H), 3.3.80 (s, 2H), 3.62 (s, 3H), 2.90 (s, 1H), 2.05 (AcOH; s, 3H); MS (EI) for C₂₂H₂₁F₃IN₅O₂: 572 (MH⁺).

Example 3(cp)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(2S)-2-(methyloxy)cyclopentyl]amino}methyl)azetidin-3-ol): MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(cq)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1R)-2-hydroxycyclohexyl]amino}methyl)azetidin-3-ol): MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(cr)

N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)phenyl]methanesulfonamide: ¹H NMR (400 MHz, CDCl₃): 7.33 (dd, 1H), 7.22 (m, 1H), 7.08 (dd, 1H), 6.83-6.77 (m, 1H), 6.03-5.98 (m, 2H), 6.64-6.59 (m, 1H), 4.08-3.77 (br m, 5H), 2.88 (s, 3H); MS (EI) for C₂₄H₂₂F₃IN₄O₄S: 647 (MH⁺).

Example 3(cs)

3-{[(4-aminophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.44 (s, 1H), 7.39 (dd, 1H), 7.34-7.30 (m, 1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.64-6.53 (m, 5H), 4.22-4.04 (br m, 4H), 3.34 (s, 2H); MS (EI) for C₂₃H₂₀F₃IN₄O₂: 569 (MH⁺).

Example 3(ct)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxy-2-methylcyclopentyl)amino]methyl}azetidin-3-ol: MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(cu)

3-[(cyclopentylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.44 (dd, 1H), 7.36-7.31 (m, 1H), 7.30-7.24 (m, 1H), 7.09-6.99 (m, 1H), 6.64-6.57 (m, 1H), 4.17-4.10 (m, 1H), 4.01-3.91 (m, 2H), 3.87-3.79 (m, 1H), 3.07-2.97 (m, 1H), 2.75 (s, 2H), 1.92-1.79 (m, 2H), 1.75-1.62 (m, 2H), 1.61-1.47 (m, 2H), 1.37-1.22 (m, 2H). MS (EI) for C₂₂H₂₃F₃IN₃O₂: 546 (MH⁺)

Example 3(cv)

3-{[(cyclohexylmethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate (salt): ¹H NMR (400 MHz, CD₃OD): 7.46 (dd, 1H), 7.39-7.32 (m, 1H), 7.31-7.25 (m, 1H), 7.11-6.99 (m, 1H), 6.67-6.57 (m, 1H), 4.27-4.15 (m, 1H), 4.12-3.97 (m, 2H), 3.96-3.85 (m, 1H), 3 (s, 2H), 2.62 (d, 2H), 1.90 (s, 3H), 1.82-1.45 (m, 6H), 1.40-1.07 (m, 3H), 1.04-0.80 (m, 2H). MS (EI) for C₂₄H₂₇F₃IN₃O₂: 574 (MH⁺).

Example 3(cw)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(propylamino)methyl]azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): δ 8.56 (s, 1H), 7.57 (dd, 1H), 7.37 (dd, 1H), 7.32 (m, 1H), 7.18 (m, 1H), 6.67 (m, 1H), 4.03 (d, 1H), 3.89 (m, 2H), 3.69 (d, 1H), 2.59 (s, 2H), 2.42 (t, 2H), 1.90 (s, 3H), 1.32 (m, 2H), 0.81 (t, 3H); MS (EI) for C₂₀H₂₁F₃IN₃O₂: 520 (MH⁺).

Example 3(cx)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-methylpropyl)amino]methyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): δ 8.56 (s, 1H), 7.56 (dd, 1H), 7.36 (dd, 1H), 7.31 (m, 1H), 7.18 (m, 1H), 6.67 (m, 1H), 4.02 (d, 1H), 3.89 (m, 2H), 3.70 (d, 1H), 2.57 (s, 2H), 2.27 (d, 2H), 1.91 (s, 3H), 1.55 (m, 1H), 0.79 (d, 6H); MS (EI) for C₂₁H₂₃F₃IN₃O₂: 534 (MH⁺).

Example 3(cy)

methyl (2xi)-2-deoxy-2-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)-beta-D-arabino-hexopyranoside: ¹H NMR (400 MHz, d₄-methanol, ˜3:1 mixture of anomers): δ 7.46 (d, 1H), 7.34 (d, 1H), 7.28 (m, 1H), 7.04 (q, 1H), 6.62 (m, 1H), 4.19-5.92 (m, 4H), 3.87-3.78 (m, 2H), 3.68 (m, 1H), 3.56-3.18 (m, 5H), 2.99-2.82 (m, 3H), 2.56 (m, 0.25H), 2.29 (m, 0.75H) MS (EI) for C₂₄H₂₇F₃IN₃O₇: 652 (M-H).

Example 3(cz)

3-({[3-(diethylamino)propyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.38-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.09-7.00 (q, 1H), 6.66-6.58 (t, 1H), 4.24-4.16 (d, 1H), 4.11-3.99 (t, 2H), 3.92-3.85 (d, 1H), 3.10-3.02 (m, 8H), 2.99-2.96 (s, 2H), 2.92-2.87 (t, 2H), 1.93-1.87 (s, 3H), 1.27-1.20 (t, 6H); MS (EI) for C₂₄H₃₀F₃IN₄O₂: 591 (MH⁺).

Example 4 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2-hydroxyethyl)azetidine-3-carboxamide

To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylic acid (15 mg, 0.03 mmol), prepared using procedures similar to those in Example 1, in N,N-dimethylformamide (2.00 mL) was added HBTU (38 mg, 0.10 mmol). The mixture was stirred for 15 minutes at room temperature followed by the addition of 2-aminoethanol (3.6 μL, 0.06 mmol) and N-methylmorpholine (110 μL, 1.00 mmol). The mixture was allowed to stir at room temperature for 3 d, then diluted the mixture with chloroform (20 mL), and washed with water (30 mL). The aqueous phase was back extracted with chloroform (10 mL). The combined organic phases were dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by high pressure liquid chromatography to afford the title compound (9.20 mg, 58%) as the trifluoroacetic acid salt: ¹H NMR (400 MHz, CDCl₃): 8.54 (s, 1H), 7.41-7.37 (m, 1H), 7.34-7.31 (m, 1H), 7.18-7.14 (m, 1H), 6.85-6.77 (m, 1H), 6.64-6.58 (m, 1H), 4.66 (br, 1H), 4.40-4.24 (br, 3H), 3.83-3.23 (br m, 7H), 1.18 (t, 3H); MS (EI) for C₁₉H₁₇F₃IN₃O₃: 542 (MNa⁺).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared:

Example 4(a)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(3,4-dihydroxybutyl)azetidine-3-carboxamide: ¹H NMR (400 MHz, CDCl₃): 8.55 (s, 1H), 7.40 (dd, 1H), 7.31-7.35 (m, 1H), 7.14-7.18 (m, 1H), 6.78-6.84 (m, 1H), 6.59-6.65 (m, 1H), 6.14 (br s, 1H), 4.50-4.60 (m, 1H), 4.20-4.40 (m, 3H), 3.60-3.80 (m, 3H), 3.40-3.52 (m, 2H), 3.20-3.32 (m, 2H), 1.96 (br s, 1H), 1.18-1.28 (m, 2H). MS (EI) for C₂₁H₂₁F₃IN₃O₄: 562 (M-H).

Example 4(b)

N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide: ¹H NMR (400 MHz, CDCl₃): 8.53 (s, 1H), 7.39 (dd, 1H), 7.33-7.31 (m, 1H), 7.17-7.13 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.58 (m, 1H), 5.50 (m, 1H), 4.57 (br, 1H), 4.29 (br m, 3H), 3.27 (m, 3H), 1.49 (m, 1H), 1.33 (m, 2H), 0.92 (t, 3H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺), 554 (MNa⁺).

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-prop-2-en-1-ylazetidine-3-carboxamide: ¹H NMR (400 MHz, CDCl₃): 8.54 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H), 7.17.7.12 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.58 (m, 1H), 5.88-5.77 (m, 1H), 5.57 (br, 1H), 5.21-5.16 (m, 2H), 4.59 (br, 1H), 4.30 (br m, 3H), 3.9 (tt, 2H), 3.32-3.25 (m, 1H)); MS (EI) for C₂₀H₁₇F₃IN₃O₂: 516 (MH⁺), 538 (MNa⁺).

Example 4(c)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}-carbonyl)-N-ethylazetidine-3-carboxamide: ¹H NMR (400 MHz, CDCl₃): 8.54 (s, 1H), 7.38 (dd, 1H), 7.33-7.30 (m, 1H), 7.17-7.12 (m, 1H), 6.83-6.77 (m, 1H), 6.63-6.57 (m, 1H), 5.55 (br s, 1H), 4.57 (br s, 1H), 4.28 (br m, 1H), 3.36-3.29 (m, 2H), 3.27-3.20 (m, 1H), 1.15 (t, 3H); MS (EI) for C₁₉H₁₇F₃IN₃O₂: 504 (MH⁺), 526 (MNa⁺).

Example 4(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}-carbonyl)-N-(2-hydroxyethyl)azetidine-3-carboxamide: ¹H NMR (400 MHz, CDCl₃): 8.50 (s, 1H), 7.39 (dd, 1H), 7.33-7.30 (m, 1H), 7.16-7.12 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.57 (br, 1H), 4.28 (br, 3H), 3.73 (t, 2H), 3.49-3.44 (m, 2H), 3.33-3.27 (m, 1H), 2.18 (br, 1H); MS (EI) for C₁₉H₁₇F₃IN₃O₃: 542 (MNa⁺).

Example 4(e)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}-carbonyl)-N-(2-piperidin-1-ylethyl)azetidine-3-carboxamide: ¹H NMR (400 MHz, CDCl₃): 11.28 (s, 1H), 8.55 (s, 1H), 7.38 (dd, 1H), 7.33-7.30 (m, 1H), 7.15-7.10 (m, 1H), 6.82-6.76 (m, 1H), 6.63-6.58 (m, 1H), 4.42 (b, 1H), 4.26 (br m, 3H), 3.68 (br s, 2H), 3.58 (br d, 2H), 3.36 (br m, 1H) 3.17 (br s, 1H), 2.63 (m, 4H), 1.92 (m, 5H); MS (EI) for C₂₄H₂₆F₃IN₄O₂: 587 (MH⁺).

Example 4(f)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}-carbonyl)-N-phenylazetidine-3-carboxamide: ¹H NMR (400 MHz, CDCl₃): 8.52 (s, 1H), 7.50 (d, 1H), 7.41-7.27 (m, 4H), 7.16 (m, 2H), 6.85-6.78 (m, 1H), 6.65-6.59 (m, 1H), 4.37 (br, 3H), 3.43 (m, 1H); MS (EI) for C₂₃H₁₇F₃IN₃O₂: 574 (MNa⁺).

Example 4(g)

N-[2-(diethylamino)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide: ¹H NMR (400 MHz, CDCl₃): 11.43 (s, 1H), 8.90 (s, 1H), 8.55 (s, 1H), 7.39 (dd, 1H), 7.33-7.30 (m, 1H), 7.15-7.10 (m, 1H), 6.87-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.44-4.22 (m, 4H), 3.65 (m, 2H), 3.38 (m, 1H), 3.19-3.13 (m, 5H), 1.33 (t, 6H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 575 (MH⁺).

Example 4(h)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}-carbonyl)-N-[(2,3-dihydroxypropyl)oxy]azetidine-3-carboxamide: MS (EI) for C₂₀H₁₉F₃IN₃O₅: 566 (MH⁺).

Example 4(i)

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)azetidine-3-carboxamide: ¹H NMR (400 MHz, CDCl₃): 8.40 (br s, 1H), 7.35 (dd, 1H), 7.30 (br d, 1H), 7.16-7.09 (m, 1H), 6.89-6.76 (m, 2H), 6.58 (ddd, 1H), 4.58-4.40 (br, 1H), 4.27 (br t, 2H), 4.22-4.14 (br, 1H), 4.08-3.12 (m, 5H), 2.18-1.82 (br, 2H); MS (EI) for C₂₀H₁₉F₃IN₃O₄: 550 (MH⁺).

Example 4(j)

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-hydroxyazetidine-3-carboxamide: ¹H NMR (400 MHz, CDCl₃): 8.23-8.10 (b, 1H), 7.35-7.28 (m, 2H), 7.14-7.07 (m, 1H), 6.86-6.80 (m, 1H), 6.60-6.54 (m, 1H), 4.52-4.38 (b, 1H), 4.32-4.08 (m, 3H), 3.30-3.21 (m, 1H); MS (EI) for C₁₇H₁₃F₃IN₃O₃: 492 (MH⁺).

Example 5 6-({3-[dimethylamino)methyl]azetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline

A mixture of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylic acid (196 mg, 0.41 mmol), prepared using procedures similar to those in Example 1, triethylamine (58 μL, 0.41 mmol), PyBOP (213 mg, 0.41 mmol) and sodium borohydride (48 mg, 1.24 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the resultant residue was partitioned between 20% aqueous citric acid and ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a colorless residue that was purified by column chromatography. Eluting with 60% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 48 mg, 0.11 mmol (25%) of [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol as a white solid. ¹H NMR (400 MHz, CDCl₃): 7.44 (d, 1H), 7.34 (d, 1H), 7.28-7.23 (m, 1H), 7.04-6.97 (m, 1H), 4.26-4.18 (m, 1H), 4.02-3.94 (m, 2H), 3.78-3.72 (m, 1H), 3.03 (d, 2H), 3.34 (s, 1H), 2.80-2.71 (m, 1H). MS (EI) for C₁₇H₁₄F₃IN₂O: 463 (MH⁺).

A solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol (48 mg, 0.11 mmol), 1,4-diazabicyclo[2.2.2]octane (18 mg, 0.16 mmol) and methanesulfonyl chloride (10 μL, 0.13 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 15 minutes. The mixture was then partitioned between water and ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a colorless residue which was purified by column chromatography. Eluting with 70% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 28 mg, 0.05 mmol (47%) of [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methyl methanesulfonate as a colorless residue which was immediately dissolved in ethylene glycol dimethyl ether (2 mL). To the solution was added dimethylamine (excess) and the solution was stirred in a seal tube at 50° C. for 15 hours. The reaction mixture was concentrated in vacuo, and the resultant residue was purified by preparative reverse phase HPLC. Isolated product was concentrated in vacuo to afford 12 mg, 0.02 mmol (40%) of 6-({3-[dimethylamino)methyl]azetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline acetate salt as a white solid. ¹H NMR (400 MHz, DMSO): 8.54 (br s, 1H), 7.58 (d, 1H), 7.37 (d, 1H), 7.33-7.28 (m, 1H), 7.18-7.12 (m, 1H), 6.70-6.64 (m, 1H), 4.18-4.12 (m, 1H), 3.99-3.76 (m, 1H), 3.52-3.47 (m, 1H), 2.52-2.48 (m, 1H), 2.39 (d, 2H), 1.85 (s, 6H); MS (EI) for C₁₉H₁₉F₃IN₃O: 490 (MH⁺).

Using the same or analogous synthetic techniques and/or substituting with alternative reagents, the following compounds of the invention were prepared:

Example 5(a)

2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-{[(1-methylethyl)amino]methyl}azetidin-1-yl)carbonyl]aniline: ¹H NMR (400 MHz, CDCl₃): 8.54 (s, 1H), 7.40 (dd, 1H), 7.31-7.33 (m, 1H), 7.11-7.15 (m, 1H), 6.76-6.82 (m, 1H), 6.58-6.64 (m, 1H), 4.23-4.30 (m, 2H), 3.90-4.00 (m, 1H), 3.76-3.84 (m, 1H), 2.69-2.85 (m, 4H), 1.05 (d, 6H). MS (EI) for C₂₀H₂₁F₃IN₃O: 502 (M-H).

Example 5(b)

2-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-2-yl]methyl}amino)ethanol: MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 5(c)

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-2-yl]methyl}ethane-1,2-diamine: MS (EI) for C₁₉H₂₀F₃IN₄O: 505 (MH⁺).

Example 5(d)

6-({3-[dimethylamino)methyl]azetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline acetate salt: ¹H NMR (400 MHz, DMSO): 8.54 (br s, 1H), 7.58 (d, 1H), 7.37 (d, 1H), 7.33-7.28 (m, 1H), 7.18-7.12 (m, 1H), 6.70-6.64 (m, 1H), 4.18-4.12 (m, 1H), 3.99-3.76 (m, 1H), 3.52-3.47 (m, 1H), 2.52-2.48 (m, 1H), 2.39 (d, 2H), 1.85 (s, 6H); MS (EI) for C₁₉H₁₉F₃IN₃O: 490 (MH⁺).

Example 6 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (132 mg, 0.295 mmol)ures similar to those in Example 1, was dissolved in dichloromethane (8 mL) and cooled to 0° C. Dess-Martin periodinane (187 mg, 0.441 mmol) was added and the mixture was stirred at ambient for 2 h. The mixture was quenched with saturated sodium bicarbonate solution: 10% sodium thiosulfate solution (1:1; 6 mL) and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 40-50% ethyl acetate in hexanes) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (122 mg, 0.273 mmol, 93% yield): ¹H NMR (400 MHz, CDCl₃): 8.43 (br s, 1H), 7.44-7.38 (m, 1H), 7.36-7.32 (m, 1H), 7.27-7.20 (m, 1H), 6.86 (ddd, 1H), 6.64 (ddd, 1H), 4.94-4.93 (m, 4H); MS (EI) for C₁₆H₁₀F₃IN₂O₂: 447 (MH⁺).

Example 7 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol

Methyl triphenylphosphonium bromide (508 mg, 1.42 mmol) was treated with potassium tert-butoxide (159 mg, 1.42 mmol) in tetrahydrofuran (5 mL) at 0° C. for 10 minutes. 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (270 mg, 0.605 mmol), prepared using procedures similar to those described in Example 6, was dissolved in tetrahydrofuran (2 mL) and was added to the mixture. The mixture was stirred at ambient for 15 h and then the mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ethyl acetate in hexanes) gave 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-methylideneazetidin-1-yl)carbonyl]aniline (57 mg, 0.128 mmol, 21% yield): ¹H NMR (400 MHz, CDCl₃): 8.56 (br s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7.18-7.12 (m, 1H), 6.86-6.76 (m, 1H), 6.62 (ddd, 1H), 5.14-5.00 (br, 2H), 4.74 (br d, 4H); MS (EI) for C₁₇H₁₂F₃IN₂O: 445 (MH⁺).

2,3-Difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-methylideneazetidin-1-yl)carbonyl]aniline (56 mg, 0.126 mmol) and 4-methylmorpholine N-oxide (44 mg, 0.376 mmol) were dissolved in acetone/water (4:1; 10 mL) and osmium tetroxide (4 wt. % in water; 0.7 mL) was added. The solution was stirred at ambient for 4 h, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 80% ethyl acetate in hexanes) and then reverse phase HPLC gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol (17 mg, 0.036 mmol, 28% yield): ¹H NMR (400 MHz, CDCl₃): 8.43 (br s, 1H), 7.40 (dd, 1H), 7.35-7.31 (m, 1H), 7.16-7.10 (m, 1H), 6.81 (ddd, 1H), 6.61 (ddd, 1H), 4.25-4.00 (m, 4H), 3.78 (s, 2H); MS (EI) for C₁₇H₁₄F₃IN₂O₃: 479 (MH⁺).

Example 8 3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

To a solution of 4-iodo-2-(methylthio)pyrimidine (2.00 g, 7.92 mmol) in tetrahydrofuran (4.00 ml) was added isopropylmagnesium chloride (815 mg, 7.92 mmol). The mixture was allowed to stir for 1 h at 0° C., followed by the addition of 1,1-dimethylethyl 3-oxoazetidiene-1-carboxylate (1.64 g, 9.60 mmol), prepared using procedures similar to those described in Example 3. The reaction mixture was then allowed to warm to room temperature and stirred for 6 h. The mixture was quenched with 1 N hydrochloric acid (10 mL) and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO₂, hexanes/ethyl acetate) to afford 1,1-dimethylethyl 3-hydroxy-3-[2-(methylthio)pyrimidin-4-yl]azetidine-1-carboxylate (380 mg, 16%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): 8.62-8.59 (d, 1H), 7.36-7.33 (d, 1H), 5.14-5.11 (s, 1H), 4.29-4.24 (d, 2H), 4.13-4.08 (d, 2H), 2.61-2.58 (s, 3H), 1.50-1.47 (s, 9H); MS (EI) for C₁₃H₁₉N₃O₃S: 298 (MH⁺).

A solution of 1,1-dimethylethyl 3-hydroxy-3-[2-(methylthio)pyrimidin-4-yl]azetidine-1-carboxylate (480 mg, 1.62 mmol), and 3-chloroperoxybenzoic (558 mg, 3.23 mmol) acid in dichloromethane (25 mL) was stirred at room temperature for 22 h. The reaction mixture was quenched with a saturated solution of sodium thiosulfate and the pH adjusted to 7 with sodium carbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The resulting crude 1,1-dimethylethyl 3-hydroxy-3-[2-(methylsulfonyl)pyrimidin-4-yl]azetidine-1-carboxylate (524 mg, 98%) was used without further purification. ¹H NMR (400 MHz, CDCl₃): 9.01-8.97 (d, 1H), 7.96-7.93 (d, 1H), 4.57-4.53 (s, 1H), 4.31-4.27 (d, 2H), 4.23-4.18 (d, 2H), 3.42-3.39 (s, 3H), 1.50-1.47 (s, 9H); MS (EI) for C₁₃H₁₉N₃O₅S: 330 (MH⁺).

A solution of 1,1-dimethylethyl 3-hydroxy-3-[2-(methylsulfonyl)pyrimidin-4-yl]azetidine-1-carboxylate (215 mg, 0.652 mmol), and aqueous ammonia (7 mL, 28% solution) in dioxane (15 mL) within a sealed steel bomb cylinder was heated at 80° C. for 4 h. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in dichloromethane and a solution of saturated sodium carbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The resulting crude 1,1-dimethylethyl 3-(2-aminopyrimidin-4-yl)-3-hydroxyazetidine-1-carboxylate (140 mg, 100%) was used without further purification. ¹H NMR (400 MHz, CDCl₃): 8.38-8.35 (d, 1H), 6.97-6.94 (d, 1H), 5.30-5.28 (s, 2H), 4.23-4.18 (d, 2H), 4.08-4.04 (d, 2H), 1.48-1.45 (s, 9H).

To a solution of 1,1-dimethylethyl 3-(2-aminopyrimidin-4-yl)-3-hydroxyazetidine-1-carboxylate (140 mg, 0.524 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (3 ml). The reaction mixture was stirred for 2 h at room temperature. The mixture was concentrated in vacuo. The resulting crude 3-(2-aminopyrimidin-4-yl)azetidin-3-ol (87 mg, 100%) was used without further purification.

A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (201 mg, 0.512 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 3-(2-aminopyrimidin-4-yl)azetidin-3-ol (87 mg, 0.52 mmol), benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (293 mg, 0.563 mmol) and N,N-diisopropylethylamine (270 uL, 2.82 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 20 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to afford the title compound 3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (22 mg, 7%). ¹H NMR (400 MHz, CD₃OD): 8.23-8.20 (d, 1H), 7.48-7.43 (d, 1H), 7.35-7.32 (m, 2H), 7.09-7.00 (m, 1H), 6.88-6.84 (d, 1H), 6.70-6.63 (t, 1H), 4.59-4.54 (d, 1H), 4.45-4.40 (d, 1H), 4.23-4.18 (d, 1H), 3.04-3.99 (t, 1H); MS (EI) for C₂₀H₁₅F₃IN₅O₂: 542 (MH⁺).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared:

Example 8(a)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyridin-2-ylazetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 8.47 (m, 1H), 7.80 (m, 1H), 7.65 (d, 1H), 7.44 (m, 1H), 7.33 (m, 3H), 7.04 (m, 1H), 6.65 (m, 1H), 4.61 (d, 1H), 4.44 (d, 1H), 4.29 (d, 1H), 4.12 (d, 1H). MS (EI) for C₂₁H₁₅F₃IN₃O₂: 526 (MH⁺).

Example 8(b)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-2-yl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.42 (m, 1H), 7.37 (m, 1H), 7.32 (m, 1H), 7.02 (m, 3H), 6.63 (m, 1H), 4.65 (d, 1H), 4.42 (d, 1H), 4.33 (d, 1H), 4.16 (d, 1H). MS (EI) for C₁₉H₁₄F₃IN₄O₂: 515 (MH⁺).

Example 8(c)

3-(1H-benzimidazol-2-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.55 (br s, 2H), 7.42 (m, 2H), 7.33 (m, 1H), 7.23 (m, 2H), 7.04 (m, 1H), 6.65 (m, 1H), 4.76 (d, 1H), 4.57 (d, 1H), 4.43 (d, 1H), 4.25 (d, 1H). MS (EI) for C₂₃H₁₆F₃IN₄O₂: 565 (MH⁺).

Example 8(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(5-methyl-1H-imidazol-2-yl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.41 (m, 1H), 7.36 (m, 1H), 7.31 (m, 1H), 7.02 (m, 1H), 6.67 (br s, 1H), 6.63 (m, 1H), 4.63 (d, 1H), 4.39 (d, 1H), 4.30 (d, 1H), 4.13 (d, 1H), 2.18 (s, 3H). MS (EI) for C₂₀H₁₆F₃IN₄O₂: 529 (MH⁺).

Example 8(e)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-prop-2-en-1-ylazetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.47 (br s, 1H), 7.40 (dd, 1H), 7.35-7.31 (m, 1H), 7.15-7.10 (m, 1H), 6.81 (ddd, 1H), 6.62 (ddd, 1H), 5.84-5.72 (m, 1H), 5.27-5.20 (m, 2H), 4.22-3.94 (m, 4H), 2.52 (d, 2H), 2.25 (s, 1H); MS (EI) for C₁₉H₁₆F₃IN₂O₂: 489 (MH⁺).

Example 8(f)

3-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]propane-1,2-diol: ¹H NMR (400 MHz, CDCl₃): 8.43 (br s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7.16-7.10 (m, 1H), 6.82 (ddd, 1H), 6.61 (ddd, 1H), 4.31-3.91 (m, 5H), 3.68 (br d, 1H), 3.54-3.49 (m, 1H), 2.01-1.80 (m, 2H); MS (EI) for C₉H₁₈F₃IN₂O₄: 523 (MH⁺).

Example 8(g)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-ethenylazetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.48 (br s, 1H), 7.40 (dd, 1H), 7.35-7.31 (m, 1H), 7.17-7.11 (m, 1H), 6.81 (ddd, 1H), 6.62 (ddd, 1H), 6.15 (dd, 1H), 5.39 (d, 1H), 5.28 (d, 1H), 4.30-4.10 (m, 4H); MS (EI) for C₁₈H₁₄F₃IN₂O₂: 475 (MH⁺).

Example 8(h)

1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethane-1,2-diol hydrochloride: ¹H NMR (400 MHz, d₆-DMSO): 8.66 (d, 1H), 7.58 (dd, 1H), 7.38 (d, 1H), 7.33-7.27 (m, 1H), 7.17 (q, 1H), 6.74-6.65 (m, 1H), 4.50-3.58 (br, 3H), 4.29 (dd, 1H), 4.14 (dd, 1H), 3.87 (t, 1H), 3.66 (t, 1H), 3.56-3.32 (m, 3H); MS (EI) for C₁₈H₁₆F₃IN₂O₄: 509 (MH⁺).

Example 8(i)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-ethylazetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.23 (br s, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.15-7.10 (m, 1H), 6.85-6.79 (m, 1H), 6.64-6.58 (m, 1H), 4.14-3.94 (m, 4H), 1.78 (q, 2H), 0.96 (t, 3H); MS (EI) for C₁₋₈H₁₆F₃IN₂O₂: 477 (MH⁺).

Example 8(j)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-methylazetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.31 (br s, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.15-7.11 (m, 1H), 6.85-6.78 (m, 1H), 6.65-6.59 (m, 1H), 4.24-4.04 (m, 4H), 1.55 (s, 3H); MS (EI) for C₁₇H₁₄F₃IN₂O₂: 463 (MH⁺).

Example 8(k)

3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 8.22-8.20 (d, 1H), 7.48-7.43 (d, 1H), 7.38-7.30 (m, 1H), 7.09-7.01 (q, 1H), 6.88-6.84 (d, 1H), 6.70-6.61 (t, 1H), 4.59-4.54 (d, 1H), 4.44-4.39 (d, 1H), 4.23-4.19 (d, 1H), 4.05-3.99 (d, 1H), 3.90-3.81 (d, 1H), 1.99-1.97 (s, 3H); MS (EI) for C₂₀H₁₅F₃, N₅O₂: 542 (MH⁺).

Example 8(m)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-pyrrol-2-yl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.37 (dd, 1H), 7.31-7.23 (m, 2H), 7.07-6.97 (m, 1H), 6.73-6.68 (m, 1H), 6.65-6.56 (m, 1H), 6.06-5.98 (m, 2H), 4.49-4.40 (m, 1H), 4.32-4.18 (m, 2H), 4.15-88-4.07 (m, 1H). MS (EI) for C₂₀H₁₅F₃IN₃O₂: 514 (MH⁺).

Example 8(n)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-methyl-1H-imidazol-2-yl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.34 (dd, 1H), 7.31-7.25 (m, 1H), 7.23-7.18 (m, 1H), 7.11-7.09 (m, 1H), 7.06-6.97 (m, 1H), 6.89-6.86 (m, 1H), 6.62-6.55 (m, 1H), 4.88-4.80 (m, 1H), 4.52-4.44 (m, 1H), 4.38-4.30 (m, 1H), 4.21-4.12 (m, 1H), 3.68 (s, 3H). MS (EI) for C₂₀H₁₆F₃IN₄O₂: 529 (MH⁺).

Example 9 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (25 mg, 0.056 mmol), prepared using procedures described in Example 6, was taken into DMF (0.5 mL) followed by addition of (trifluoromethyl)trimethylsilane (40 μL, 0.28 mmol) and cesium carbonate (22 mg, 0.067 mmol) and the mixture was stirred for one hour at room temperature. The mixture was partitioned with ethyl ether and water and the organic phase washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:2 as eluent afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol (19.8 mg, 69% yield) as a colorless crystalline solid. ¹H-NMR (400 MHz, CDCl₃): 8.31-8.26 (br, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.13-7.10 (m, 1H), 6.86-6.80 (m, 1H), 6.65-6.60 (m, 1H), 4.42 (br s, 2H), 4.18 (br s, 2H). MS (EI) for C₁₇H₁₁F₆IN₂O₂: 517 (MH⁺).

Example 10 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one oxime

To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (100 mg, 0.22 mmol), prepared using procedures similar to those described in Example 6, in dioxane (1.0 mL) was added hydroxylamine (0.10 mL, 50% solution in water, 1.5 mmol), and the resulting solution was heated at 60° C. for 18 h. The mixture was cooled to room temperature and the crude product was purified by reverse phase HPLC to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one oxime (56 mg, 54% yield): ¹HNMR (400 MHz, CDCl₃), 8.43 (br s), 7.43-7.39 (m, 2H), 7.35-7.32 (dd, 1H), 7.19-7.15 (m, 1H), 6.87-6.81 (m, 1H), 6.65-6.59 (m, 1H), 4.89 (br s, 2H), 4.85 (br s, 2H); MS (EI) for C₁₆H₁₁F₃IN₃O₂: 462 (MH⁺).

Example 11 N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine

To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (0.09 M in acetonitrile, 500 μL, 0.045 mmol), prepared using procedures similar to those described in Example 2, was added triethylamine (20 μL, 0.135 mmol) and n-butylbromide (6.14 μL, 0.054 mmol) followed by additional acetonitrile (1.0 mL). The reaction mixture was stirred at room temperature for 16 h, at which time it was purified directly by reverse phase HPLC to afford the title compound (8.4 mg). ¹H NMR (400 MHz, CDCl₃): 8.50 (s, 1H), 7.39 (dd, 1H), 7.32 (dd, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.35 (br s, 2H), 4.00 (br s, 1H), 3.87 (br s, 1H), 3.74-3.68 (m, 1H), 3.20 (br s, 3.5H), 2.56 (t, 2H), 2.03 (s, 2H), 1.50-1.42 (m, 2H), 1.39-1.29 (m, 2H), 0.91 (t, 3H). MS (EI) for C₂₀H₂₁F₃IN₃O: 504 (MH⁺).

Example 12 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methylazetidin-3-amine

To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (0.10 M in acetonitrile, 1.0 mL, 0.09 mmol), prepared using procedures similar to those described in Example 2, in 1:1 ratio of methanol and tetrahydrofuran (2.0 mL) was added formaldehyde (37% wt, 6.7 μL, 0.09 mmol) followed by sodium cyanoborohydride (11.0 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 16 h, at which time it was quenched with saturated aqueous ammonium chloride. The solution was then purified directly by reverse phase HPLC to afford the title compound (14.9 mg). ¹H NMR (400 MHz, CDCl₃): 8.13 (br s, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 7.09-7.04 (m, 1H), 6.84-6.78 (m, 1H), 6.60-6.54 (m, 1H), 4.46-4.33 (br m, 4H), 3.93 (br m, 1H), 2.64 (s, 3H). MS (EI) for C₁₇H₁₅F₃IN₃O: 462 (MH⁺).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared:

Example 12(a)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methylazetidin-3-amine: ¹H NMR (400 MHz, CDCl₃): 8.13 (br s, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 7.09-7.04 (m, 1H), 6.84-6.78 (m, 1H), 6.60-6.54 (m, 1H), 4.46-4.33 (br m, 4H), 3.93 (br m, 1H), 2.64 (s, 3H). MS (EI) for C₁₇H₁₅F₃IN₃O: 462 (MH⁺).

Example 12(b)

2-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]amino}ethanol: ¹H NMR (400 MHz, CDCl₃): 8.20 (s, 1H), 7.36 (d, 1H), 7.30 (d, 1H), 7.13-7.09 (m, 1H), 6.85-6.79 (m, 1H), 6.61-6.55 (m, 1H), 4.43 (br m, 3H), 3.98 (br m, 1H), 3.87 (br m, 1H), 3.02 (br m, 1H), 1.24-1.20 (m, 1H). MS (EI) for C₁₈H₁₇F₃IN₃O₂: 492 (MH⁺).

Example 12(c)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]propane-1,3-diamine: ¹H NMR (400 MHz, CDCl₃): 8.51 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.33 (br s, 2H), 3.99 (br s, 1H), 3.84 (br s, 1H), 3.71-3.64 (m, 1H), 2.91 (t, 2H), 2.70-2.66 (m, 2H), 2.01 (s, 4H), 1.76-1.69 (m, 2H). MS (EI) for C₁₉H₂₀F₃IN₄O: 505 (MH⁺).

Example 12(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-ethylazetidin-3-amine: ¹H NMR (400 MHz, CDCl₃): 8.47 (s, 1H), 7.38 (d, 1H), 7.31 (d, 1H), 7.13-7.09 (m, 1H), 6.83-6.77 (m, 1H), 6.62-6.57 (m, 1H), 4.49 (br s, 3H), 4.36 (br s, 2H), 4.08 (br s, 1H), 3.94 (br s, 1H), 3.77-3.72 (m, 1H), 2.69-2.63 (m, 2H), 1.99 (s, 2H), 1.14 (t, 3H). MS (EI) for C₁₈H₁₇F₃IN₃O: 476 (MH⁺).

Example 12(e)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2-methylpropyl)azetidin-3-amine: ¹H NMR (400 MHz, CDCl₃): 8.50 (s, 1H), 7.38 (d, 1H), 7.31 (d, 1H), 7.14-7.09 (m, 1H), 6.83-6.76 (m, 1H), 6.63-6.57 (m, 1H), 4.34 (br s, 2H), 4.00 (br s, 1H), 3.86 (br s, 1H), 3.71-3.66 (m, 1H), 3.42 (br s, 2H), 2.36 (d, 2H), 2.00 (s, 1H), 1.75-1.65 (m, 1H), 0.91 (d, 6H). MS (EI) for C₂₀H₂₁F₃IN₃O: 504 (MH⁺).

Example 12(f)

N-(cyclopropylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine: ¹H NMR (400 MHz, CDCl₃): 8.48 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 5.78 (s, 3H), 4.36 (br s, 2H), 4.10 (br s, 1H), 3.94 (br s, 1H), 3.81-3.75 (m, 1H), 2.49 (d, 2H), 2.01 (s, 4H), 0.94-0.86 (m, 1H), 0.53 (d, 2H), 0.13 (d, 2H). MS (EI) for C₂₀H₁₉F₃IN₃O: 502 (MH⁺).

Example 12(g)

N-(cyclohexylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine: ¹H NMR (400 MHz, CDCl₃): 8.48 (s, 1H), 7.38 (dd, 1H), 7.31 (d, 1H), 7.13-7.08 (m, 1H), 6.83-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.55 (br s, 2H), 4.33 (br m, 2H), 4.02 (br s, 1H) 3.87 (br s, 1H), 3.71-3.65 (m, 1H), 2.38 (d, 2H), 1.74-1.68 (m, 4H), 1.46-1.36 (m, 1H), 1.27-1.12 (m, 3H), 0.94-0.84 (m, 2H). MS (EI) for C₂₃H₂₅F₃IN₃O: 544 (MH⁺).

Example 12(h)

N-(cyclopentylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine: ¹H NMR (400 MHz, CDCl₃): 8.32 (s, 1H), 7.37 (d, 1H), 7.31 (d, 1H), 7.11-7.07 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.44-4.37 (m, 3H), 4.02-3.96 (m, 1H), 2.84 (d, 2H), 2.54 (br s, 5H), 2.20-2.12 (m, 1H), 1.88-1.81 (m, 2H), 1.68-1.54 (m, 4H), 1.24-1.15 (m, 2H). MS (EI) for C₂₂H₂₃F₃IN₃O: 530 (MH⁺).

Example 13 1-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine

2,4,6-Trifluorobenzoic acid (643 mg, 3.65 mmol) and 2-fluoro-4-iodoaniline (1.0 g, 4.22 mmol) were taken into acetonitrile (30 mL) followed by addition of lithium amide (290 mg, 12.7 mmol) and the mixture was heated to 60° C. under a nitrogen atmosphere for one hour. On cooling to room temperature the mixture was added to 1 N aqueous hydrochloric acid (100 mL) and the precipitate formed was collected by filtration and washed once with water then hexanes and dried in vacuo to give 2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (849 mg, 59% yield) as a tan solid. ¹H-NMR (400 MHz, D₆-DMSO): 13.72 (br s, 1H), 9.46 (s, 1H), 7.75 (d, 1H), 7.56 (d, 1H) 7.28 (tr, 1H), 6.73-6.67 (m, 1H), 6.53 (d, 1H).

2,4-Difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 μL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [1-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (125 mg) as a colorless oil.

The oil was taken into trifluoroacetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated then the residue taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane until the solution was acidic. The solution was concentrated and the residue triturated with ethyl ether to give a thick precipitate. The solid was collected by filtration and dried in vacuo to give 1-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine hydrochloride (58 mg, 48% overall yield). ¹H-NMR (400 MHz, D₆-DMSO): 8.67 (br s, 3H), 8.45 (s, 1H), 7.71 (d, 1H), 7.54 (d, 1H), 7.25 (tr, 1H), 6.77 (tr, 1H), 6.48 (d, 1H), 4.28-4.23 (m, 2H), 4.13-4.06 (m, 3H). MS (EI) for C₁₆H₁₃F₃IN₃O: 448 (MH⁺).

Example 14 1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine

2,4,5-Trifluorobenzoic acid (643 mg, 3.65 mmol) and 2-fluoro-4-iodoaniline (1.0 g, 4.22 mmol) were taken into acetonitrile (30 mL) followed by addition of lithium amide (290 mg, 12.7 mmol) and the mixture was heated to 60° C. under a nitrogen atmosphere for one hour. On cooling to room temperature the mixture was added to 1 N aqueous hydrochloric acid (100 mL) and the precipitate formed was collected by filtration and washed once with water then hexanes and dried in vacuo to give 4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (624 mg, 43% yield) as a tan solid. ¹H-NMR (400 MHz, D₆-DMSO): 13.65 (br s, 1H), 9.63 (s, 1H), 7.84 (tr, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.32 (tr, 1H), 7.03-6.98 (dd, 1H).

4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 μL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (131 mg) as a colorless oil. The oil was taken into trifluoroacetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated then the residue taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane until the solution was acidic. The solution was concentrated and the residue triturated with ethyl ether to give a thick precipitate. The solid was collected by filtration and dried in vacuo to give 1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine hydrochloride (67 mg, 55% overall yield). ¹H-NMR (400 MHz, D₆-DMSO): 9.02 (s, 1H), 8.54 (br s, 3H), 7.68 (dd, 1H), 7.53-7.47 (m, 2H), 7.22 (tr, 1H), 7.16 (dd, 1H), 4.60 (br s, 1H), 4.23 (br s, 2H), 4.03 (br m, 2H). MS (EI) for C₁₆H₁₃F₃IN₃O: 448 (MH⁺).

Example 15 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)-3-hydroxyazetidine-3-carboxamide

1-(Diphenylmethyl)azetidin-3-ol hydrochloride (2.75 g, 9.98 mmol), prepared using procedures similar to those described for Scheme 1 of the General Synthetic Section, 3 Å molecular sieves and 4-methylmorpholine (1.1 mL, 10.0 mmol) were suspended in dichloromethane (20 mL) at 0° C. 4-Methylmorpholine N-oxide (2.93 g, 25.0 mmol) and tetrapropylammonium perruthenate (140 mg, 0.399 mmol) were added and the mixture was stirred at ambient for 24 h. The mixture was filtered through a plug of silica using 5% triethylamine in ethyl acetate as eluent. The filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 8:1 hexanes:ethyl acetate) gave 1-(diphenylmethyl)azetidin-3-one (871 mg, 3.68 mmol, 37% yield): ¹H NMR (400 MHz, CDCl₃): 7.50-7.46 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 4.59 (s, 1H), 4.01 (s, 4H); MS (EI) for C₁₆H₁₅NO: 238 (MH⁺).

1-(Diphenylmethyl)azetidin-3-one (600 mg, 2.53 mmol), was dissolved in dichloromethane (1 mL) and treated with triethylamine (0.5 mL, 3.59 mmol) and trimethylsilylcyanide (0.8 mL, 6.01 mmol) at ambient for 2 h and then the mixture was concentrated in vacuo to afford 1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (774 mg, 2.30 mmol, 91% yield) as a yellow solid. 1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (250 mg, 0.744 mmol) was dissolved in dichloromethane (2 mL) at 0° C. and concentrated sulfuric acid (0.2 mL) was added dropwise. The mixture was stirred at ambient for 2 h and then was cooled to 0° C. and 25% ammonium hydroxide solution was added carefully dropwise to pH ˜10-11. The mixture was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a residue which was triturated with hexanes/ether to afford 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide (160 mg, 0.567 mmol, 76% yield) as an off-white solid: ¹H NMR (400 MHz, CDCl₃): 7.92 (br s, 1H), 7.39-7.34 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 5.61 (br s, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 3.50 (dd, 2H), 3.20 (dd, 2H); MS (EI) for C₁₇H₁₈N₂O₂: 283 (MH⁺).

1-(Diphenylmethyl)-3-hydroxyazetidine-3-carboxamide (1.1 g, 3.90 mmol) was treated with 10% sodium hydroxide in ethanol (15 mL) and water (2 mL) at reflux for 2 h and then was concentrated in vacuo. The residue was neutralized with 1 N hydrochloric acid (pH ˜7) and the precipitate was collected by filtration and lyophilized to afford 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxylic acid (assume 3.90 mmol) which was used without further purification: ¹H NMR (400 MHz, d₆-DMSO): 7.45-7.40 (m, 4H), 7.31-7.25 (m, 4H), 7.21-7.15 (m, 2H), 4.52 (s, 1H), 3.46 (dd, 2H), 3.02 (dd, 2H); MS (EI) for C₁₇H₁₇NO₃: 284 (MH⁺).

1-(Diphenylmethyl)-3-hydroxyazetidine-3-carboxylic acid (assume 3.90 mmol) was suspended in methanol (40 mL) and 4 N hydrochloric acid in dioxane (1 mL, 4 mmol) was added. 20 wt % Palladium hydroxide on carbon (100 mg) was added to the solution and the mixture was treated with hydrogen at 40 psi for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 3-hydroxyazetidine-3-carboxylic acid hydrochloride which was dissolved in tetrahydrofuran (5 mL) and water (5 mL) and treated with potassium carbonate (1.615 g, 11.7 mmol) and di-tert-butyl dicarbonate (935 mg, 4.29 mmol) were added. The mixture was stirred at ambient for 17 h and then the mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate and then was acidified to pH ˜3-4 and extracted twice more with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-hydroxyazetidine-3-carboxylic acid which was dissolved in DMF (3 mL). Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (2.028 g, 3.90 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.03 mmol) were added. The mixture was stirred at ambient for 5 minutes and then allylamine (0.6 mL, 8.03 mmol) was added and the mixture was stirred for 17 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave 1,1-dimethylethyl 3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782 mg, 3.05 mmol, 78% yield from 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide). 1,1-Dimethylethyl 3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782 mg, 3.05 mmol) was dissolved in methanol (10 mL) and 4 N hydrochloric acid in dioxane (2 mL, 8 mmol) was added. The mixture was refluxed for 15 minutes and then was concentrated in vacuo to afford 3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide hydrochloride (3.05 mmol).

3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (1.20 g, 3.05 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (1.20 g, 9.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (701 mg, 3.66 mmol) were dissolved in DMF (10 mL). The mixture was stirred at ambient for 5 minutes and then 3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide hydrochloride (3.05 mmol) in DMF (5 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 60-85% ethyl acetate in hexanes) and then reverse phase HPLC gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide (150 mg, 0.282 mmol, 9% yield): ¹H NMR (400 MHz, d₆-DMSO): 8.64 (br s, 1H), 8.13 (t, 1H), 7.58 (dd, 1H), 7.38 (dd, 1H), 7.34-7.28 (m, 1H), 7.21-7.12 (m, 1H), 6.84 (br s, 1H), 6.72 (ddd, 1H), 5.83-5.72 (m, 1H), 5.10-4.99 (m, 2H), 4.38 (d, 1H), 4.20 (d, 1H), 4.02 (d, 1H), 3.86 (d, 1H), 3.73-3.68 (m, 2H); MS (EI) for C₂₀H₁₇F₃IN₃O₃: 532 (MH⁺).

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide (88 mg, 0.166 mmol) and 4-methylmorpholine N-oxide (58 mg, 0.496 mmol) were dissolved in acetone/water (4:1; 10 mL) and osmium tetroxide (2.5 wt. % in water; 0.1 mL) was added. The solution was stirred at ambient for 15 h, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase HPLC gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)-3-hydroxyazetidine-3-carboxamide (68 mg, 0.120 mmol, 72% yield): ¹H NMR (400 MHz, d₆-DMSO): 8.65 (br s, 1H), 7.72 (t, 1H), 7.58 (dd, 1H), 7.41-7.36 (m, 1H), 7.34-7.28 (m, 1H), 7.21-7.12 (m, 1H), 6.92 (br s, 1H), 6.72 (ddd, 1H), 5.00-4.10 (br, 2H), 5.10-4.99 (m, 2H), 4.39 (d, 1H), 4.20 (d, 1H), 4.02 (d, 1H), 3.54-3.45 (m, 1H), 3.34-3.21 (m, 2H), 3.06-2.96 (m, 1H); MS (EI) for C₂₀H₁₉F₃IN₃O₅: 566 (MH⁺).

Example 15(a)

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-carboxamide: ¹H NMR (400 MHz, d₆-DMSO): 8.63 (br s, 1H), 7.58 (dd, 1H), 7.42-7.36 (m, 3H), 7.34-7.28 (m, 1H), 7.22-7.12 (m, 1H), 6.76-6.68 (m, 2H), 4.39 (d, 1H), 4.19 (d, 1H), 4.00 (d, 1H), 3.83 (d, 1H); MS (EI) for C₁₇H₁₃F₃IN₃O₃: 492 (MH⁺).

Example 16 6-{[3-(aminomethyl)-3-(methyloxy)azetidin-1-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline

Phenylmethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (165 mg, 0.75 mmol), prepared using procedures similar to those described in Reference 3, in THF (1 mL) was added to anhydrous ammonia saturated in THF (10 mL) and the mixture was allowed to stir in a sealed vessel at room temperature over 24 hours. The solution was then concentrated and taken back into THF (1 mL) followed by addition of di-tert-butyldicarbonate (164 mg, 0.75 mmol) and stirred for one hour at room temperature. The mixture was then concentrated and the residue purified by silica gel flash chromatography using hexanes:ethyl acetate (1:1) as eluent to give phenylmethyl 3-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3-hydroxyazetidine-1-carboxylate (16.5 mg, 7% yield) and unreacted epoxide (120 mg, 73% recovery). ¹H-NMR (400 MHz, CDCl₃): 7.34 (m, 5H), 5.10 (br, 1H), 5.09 (s, 2H), 4.68 (s, 1H), 3.90 (dd AB, 4H), 3.41 (d, 2H), 1.44 (s, 9H).

Phenylmethyl 3-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3-hydroxyazetidine-1-carboxylate (16.5 mg, 0.05 mmol) and 10% Pd/C (8 mg) were taken into methanol (2 mL) and hydrogenated at ambient pressure over 12 hours. The catalyst was removed by filtration and the filtrate concentrated and dried in vacuo. The residue was taken into THF (1 mL) followed by addition of DIPEA (10 μL, 0.06 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (19.8 mg, 0.05 mmol), prepared using procedures similar to those described in Reference 1, and the solution was stirred at room temperature for 30 minutes. Concentration and purification of the residue by silica gel flash chromatography using hexanes:ethyl acetate (1:1.5) afforded 1,1-dimethylethyl {[1-({3,4-difluoro-2[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-yl]methyl}carbamate (19 mg, 66% yield).

1,1-Dimethylethyl {[1-({3,4-difluoro-2[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-yl]methyl}carbamate (8.0 mg, 0.014 mmol) and silver (I) oxide (12 mg, 0.05 mmol) were taken into methyl iodide (0.5 mL) and the mixture was brought to reflux for 4 hours. The suspension was then cooled to room temperature and diluted with an excess of ethyl ether then filtered. The filtrate was concentrated and purified by silica gel flash chromatography using hexanes:ethyl acetate (1:1) as eluent to give 1,1-dimethylethyl {[1-({3,4-difluoro-2[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(methyloxy)azetidine-3-yl]methyl}carbamate (2 mg). The material was taken into TFA (0.5 mL) and allowed to stand for 5 minutes then concentrated in vacuo. The residue was azetroped twice from methanol (2 mL) and the residue dried in vacuo to afford 6-{[3-(aminomethyl)-3-(methyloxy)azetidin-1-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline trifluoroacetate salt (2.3 mg, 27% yield) as an amorphous solid. MS (EI) for C₁₈H₁₇F₃IN₃O: 492 (MH⁺).

Example 17 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{(2-[(1-methylethyl)amino]ethyl}azetidin-3-ol

A solution of tert-butyl acetate (566 μL, 4.2 mmol) in THF (10 mL) was cooled to −78° C. To the solution was added LHMDS (5.25 mL of a 1.0 M solution in hexanes, 5.25 mmol), and the resulting mixture was stirred for 20 min at −78° C. To the solution was added 1-(diphenylmethyl)azetidin-3-one (500 mg, 2.1 mmol), prepared using procedures similar to those described in Example 15. After stirring for 1 h, saturated aqueous ammonium chloride was added, and the mixture was warmed to rt. Water and ether were added, and the resulting biphasic mixture was partitioned. The aqueous phase was extracted once with ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (80% hexanes:20% ethyl acetate) to provide 1,1-dimethylethyl [1-(diphenylmethyl)-3-hydroxyazetidin-3-yl]acetate as a pale yellow solid (644 mg, 1.8 mmol, 87% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.40 (m, 4H), 7.26 (m, 4H), 7.19 (m, 2H), 4.40 (s, 1H), 4.02 (s, 1H), 3.15 (m, 2H), 3.05 (m, 2H), 2.83 (s, 2H), 1.45 (s, 9H).

To a solution of 1,1-dimethylethyl [1-(diphenylmethyl)-3-hydroxyazetidin-3-yl]acetate (333 mg, 0.94 mmol) in THF (3 mL) at 0° C. was added lithium aluminum hydride (940 μL of a 1.0 M solution in THF, 0.94 mmol). The mixture was stirred for 3 h 20 min while warming to rt. Water (36 μL) was added carefully to the solution, followed by 15% sodium hydroxide (36 μL) and more water (108 μL). The resulting precipitate was removed by filtration through celite, and the filtrate was concentrated to dryness yielding 1-(diphenylmethyl)-3-(2-hydroxyethyl)azetidin-3-ol (228 mg, 0.80 mmol, 85% yield) as a colorless syrup. ¹H NMR (400 MHz, CDCl₃): δ 7.38 (m, 4H), 7.26 (m, 4H), 7.19 (m, 2H), 4.37 (s, 1H), 3.92 (m, 2H), 3.32 (m, 2H), 2.96 (m, 2H), 2.07 (m, 2H).

Palladium hydroxide (100 mg) was suspended in a solution of 1-(diphenylmethyl)-3-(2-hydroxyethyl)azetidin-3-ol (228 mg, 0.80 mmol) in methanol (15 mL), and the mixture was subjected to an atmosphere of hydrogen at 50 psi for 4 h. The catalyst was then removed by filtration through celite, and the filtrate was concentrated in vacuo to provide 3-(2-hydroxyethyl)azetidin-3-ol. This material was used in the subsequent reaction without purification. To a solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (314 mg, 0.80 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, in DMF (4 mL) was added PyBOP (416 mg, 0.80 mmol) and triethylamine (223 μL, 1.6 mmol). Finally, the unpurified 3-(2-hydroxyethyl)azetidin-3-ol was added, and the resulting mixture was stirred at rt for 16 h. Water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted with once more with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography, eluting with ethyl acetate, to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxyethyl)azetidin-3-ol as a colorless oil (303 mg, 0.62 mmol, 78% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.46 (s, 1H), 7.39 (dd, 1H), 7.32 (m, 1H), 7.13 (m, 1H), 6.81 (m, 1H), 6.60 (m, 1H), 4.37 (br s, 1H), 4.28 (br m, 4H), 3.94 (br s, 2H), 2.19 (br s, 1H), 2.02 (m, 2H); MS (EI) for C₁₈H₁₆F₃IN₂O₃: 491 (MH⁻).

A solution of oxalyl chloride (13 μL, 0.15 mmol) in dichloromethane (1 mL) was cooled to −78° C., and DMSO (22 μL, 0.31 mmol) was then added. To this mixture was added 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxyethyl)azetidin-3-ol (67.8 mg, 0.14 mmol) as a suspension in dichloromethane (1 mL). After stirring at −78° C. for 10 min, triethylamine (78 μL, 0.56 mmol) was added and the mixture was allowed to warm to rt. The solution was diluted with dichloromethane, and washed with 0.5 N HCl. The aqueous phase wash then extracted with dichloromethane. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to provide [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]acetaldehyde as a white solid (22.1 mg, 0.045 mmol, 32% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.82 (s, 1H), 8.46 (s, 1H), 7.39 (m, 1H), 7.33 (m, 1H), 7.11 (m, 1H), 6.81 (m, 1H), 6.61 (m, 1H), 4.32-3.96 (br m, 4H), 3.41 (t, 2H), 3.07 (s, 1H); MS (EI) for C₁₈H₁₄F₃IN₂O₃: 491 (MH⁺).

To a solution of [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]acetaldehyde (38.0 mg, 0.078 mmol) in 1,2-dichloroethane (1 mL) was added isopropylamine (27 μL, 0.31 mmol) followed by sodium triacetoxyborohydride (26 mg, 0.12 mmol). The mixture was stirred for 3 h before quenching with 1 drop of concentrated HCl. The quenched mixture was concentrated to dryness, and then purified by preparative HPLC to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{2-[(1-methylethyl)amino]ethyl}azetidin-3-ol (21.5 mg) as a pale yellow solid. ¹H NMR (400 MHz, d₆-DMSO): δ 8.54 (s, 1H), 7.57 (dd, 1H), 7.38 (dd, 1H), 7.31 (m, 1H), 7.17 (m, 1H), 6.67 (m, 1H), 4.02 (m, 1H), 3.89 (m, 2H), 3.71 (m, 1H), 2.70 (m, 1H), 2.63 (m, 2H), 1.86 (s, 3H), 1.75 (m, 2H), 0.97 (d, 6H); MS (EI) for C₂₁H₂₃F₃IN₃O₂: 534 (MH⁺).

Example 18 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1,1-dimethyl-2-[(1-methylethyl)amino]ethyl}azetidin-3-ol

To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (500 mg, 1.12 mmol), prepared using procedures similar to those described in Example 6, in dichloromethane (5 mL) cooled to 0° C. was added titanium tetrachloride (125 μL, 1.12 mmol). The dark brown solution was stirred at 0° C. for 45 minutes, followed by the addition of methyltrimethylsilyl dimethylketene acetal (550 μL, 2.24 mmol) at 0° C. Upon addition the solution was allowed to warm to room temperature, and was stirred for 1 hour. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil which was purified by column chromatography. Eluting with 10% diethyl ether in dichloromethane, the isolated product was concentrated in vacuo to afford 520 mg, 0.95 mmol (85%) of methyl 2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoate as a white foam. ¹H NMR (400 MHz, CDCl₃): 8.34 (s, 1H), 7.38 (d, 1H), 7.31 (d, 1H), 7.13-7.08 (m, 1H), 6.85-6.77 (m, 1H), 6.63-6.56 (m, 1H), 4.26-4.20 (m, 2H), 4.13-4.09 (m, 1H), 4.00-3.93 (m, 1H), 3.70 (s, 3H), 1.23 (s, 6H). MS (EI) for C₂₁H₂₀F₃IN₂O₄: 547 (MH⁻).

A solution of methyl 2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoate (520 mg, 0.95 mmol) in 4N aqueous potassium hydroxide (5 mL) was stirred at 50° C. for 1 hour. Using concentrated aqueous hydrochloric acid, the reaction mixture was acidified to pH 5, and then partitioned with ethyl acetate. The aqueous portion was extracted twice using ethyl acetate, and the combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 300 mg, 0.56 mmol (59%) of 2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoic acid as a white solid. ¹H NMR (400 MHz, DMSO): 8.49 (s, 1H), 7.57-7.52 (m, 1H), 7.37-7.25 (m, 2H), 7.17-7.13 (m, 1H), 6.68-6.58 (m, 1H), 3.98-3.94 (m, 2H), 3.80-3.77 (m, 1H), 3.55-3.52 (m, 1H), 0.88 (s, 6H). MS (EI) for C₂₀H₁₈F₃IN₂O₄: 535 (MH⁺).

To solution of 2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoic acid (300 mg, 0.56 mmol) in tetrahydrofuran (5 mL) was added triethylamine (80 μL, 0.56 mmol), followed by PyBOP (295 mg, 0.56 mmol) and finally sodium borohydride (64 mg, 1.68 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding 20% aqueous citric acid, and then partitioned with ethyl acetate. The organic portion was washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a white solid which was purified by column chromatography. Eluting with 60% ethyl acetate in hexanes, the isolated product was concentrated in vacuo to afford 238 mg, 0.46 mmol (82%) of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxy-1,1-dimethylethyl)azetidin-3-ol as a white solid. ¹H NMR (400 MHz, DMSO): 8.53 (s, 1H), 7.57 (d, 1H), 7.38-7.28 (m, 2H), 7.22-7.15 (m, 1H), 6.70-6.64 (m, 1H), 5.61 (s, 1H), 4.57 (br s, 1H), 4.30-4.27 (m, 1H), 4.18-4.15 (m, 1H), 3.80-3.77 (m, 1H), 3.68-3.64 (m, 1H), 3.25 (s, 2H), 0.76 (d, 6H); MS (EI) for C₂₀H₂₀F₃IN₂O₃: 521 (MH⁺).

A mixture of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxy-1,1-dimethylethyl)azetidin-3-ol (200 mg, 0.38 mmol) and Dess-Martin periodinane (240 mg, 0.57 mmol) in dichloromethane (2 mL) was stirred at room temperature for 2 hours. 10% aqueous sodium thiosulfate (2 mL), and saturated aqueous sodium bicarbonate (2 mL) was added and the mixture was stirred at room temperature for 15 minute. The mixture was partitioned and the aqueous layer was extracted twice using dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo, to afford a white solid which was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes, the isolated product was concentrated in vacuo to afford 100 mg, 0.20 mmol (53%) of 2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanal as a white solid, which was immediately dissolved in tetrahydrofuran (2 mL). To the solution was added isopropylamine (34 μL, 0.40 mmol), followed by triacetoxyborohydride (212 mg, 1.0 mmol). The solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and partitioned between 20% aqueous citric acid and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate, and the combined organic portion was washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by preparative reverse phase HPLC. The isolated product was concentrated in vacuo to afford 50 mg, 0.07 mmol (36%) of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1,1-dimethyl-2-[(1-methylethyl)amino]ethyl}azetidin-3-ol acetate salt as a white solid. ¹H NMR (400 MHz, DMSO): 8.47 (br s, 1H), 7.55 (d, 1H), 7.36-7.29 (m, 2H), 7.22-7.15 (m, 1H), 6.68-6.63 (m, 1H), 4.17-4.08 (m, 2H), 3.76-3.73 (m, 1H), 3.56-3.52 (m, 1H), 2.58-2.51 (m, 1H), 2.45-2.37 (m, 2H), 0.92 (t, 6H), 0.78 (d, 6H); MS (EI) for C₂₃H₂₇F₃IN₃O₂: 562 (MH⁺).

Example 19 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-amine

To a solution of the 1-(diphenylmethyl)-3-[(phenylmethyl)amino]azetidine-3-carbonitrile (0.80 g, 2.2 mmol), prepared using procedures similar to those described in Kozikowski and Fauq Synlett 1991, 11, 783-4, in ethanol (30 mL) was added solid sodium hydroxide (7.5 mmol), and the resulting mixture was stirred at room temperature for 3 days. Water (6 mL) was added to the reaction mixture and stirring was continued at 90° C. for 2 h. The pH of the reaction mixture was adjusted to 5 with concentrated hydrochloric acid and a white solid precipitated. The mixture was cooled, diluted with water (50 mL) and the solid was collected, washed with water then dried in vacuo to give the 1-(diphenylmethyl)-3-[(phenylmethyl)amino]azetidine-3-carboxylic acid (0.75 g, 88% yield), MS (EI) for C₂₄H₂₄N₂O₂: 373 (MH⁺).

To a mixture of 1-(diphenylmethyl)-3-[(phenylmethyl)amino]azetidine-3-carboxylic acid (0.50 g, 1.34 mmol), N,N-diisopropylethylamine (0.47 mL, 2.68 mmol) in DMF (3 mL) was added 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate (1.34 g, 2.68 mol) and the resulting mixture was stirred at room temperature for 10 minutes. To this mixture was added 2-propylamine (0.22 mL, 2.68 mmol) and stirring was continued for 18 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 2% aqueous citric acid, 5% lithium chloride, and brine solutions (50 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, eluting with 15-25% ethyl acetate-hexane) to give 1-(diphenylmethyl)-N-(1-methylethyl)-3-[(phenylmethyl)amino]azetidine-3-carboxamide (0.51 g, 92% yield), MS (EI) for C₂₇H₃₁N₃O: 414 (MH⁺).

To a solution of the 1-(diphenylmethyl)-N-(1-methylethyl)-3-[(phenylmethyl)amino]azetidine-3-carboxamide (0.40 g, 0.97 mmol) in tetrahydrofuran (10 mL) at room was added a solution of lithium aluminum hydride in tetrahydrofuran (1M, 2.90 mL, 2.90 mmol), and the resulting mixture was stirred at 50° C. for 3 h. The reaction mixture was cooled to room temperature, quenched with 20% aqueous hydroxide solution (1 mL), diluted with ether (50 mL) and filtered. The filtrate was washed with brine solution (20 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, eluting with 5% methanol-dichloromethane) to give 1-(diphenylmethyl)-3-{[(1-methylethyl)amino]methyl}-N-(phenylmethyl)azetidin-3-amine (0.35 g, 90% yield), ¹H NMR (400 MHz, CDCl₃): 7.42-7.14 (m, 15H), 4.34 (s, 1H), 3.66 (s, 2H), 3.22-3.18 (d, 2H), 2.97 (s, 2H), 2.90-2.86 (d, 2H), 2.68-2.62 (p, 1H), 1.09-1.07 (d, 6H); MS (EI) for C₂₇H₃₃N₃: 400 (MH⁺).

To a solution of the 1-(diphenylmethyl)-3-{[(1-methylethyl)amino]methyl}-N-(phenylmethyl)azetidin-3-amine (0.35 g, 0.88 mmol) in methanol was added a solution of hydrogen chloride in dioxane (4 molar solution, 0.96 mL, 4.40 mmol) and the resulting mixture was concentrated to give a white solid which was taken back into methanol. To this solution were added palladium hydroxide (20% on carbon, 0.50 g, 0.19 mmol) and the resulting mixture shaken at 50 psi in a Parr apparatus for 3 h. The reaction mixture was filtered and concentrated to give a solid, which was washed with ether and dried in vacuo to give 3-{[(1-methylethyl)amino]methyl}azetidin-3-amine hydrochloride as a white solid (0.18 g, 81% yield). MS (EI) for C₇H₁₇N₃: 144 (MH⁺).

To a mixture of the 3-{[(1-methylethyl)amino]methyl}azetidin-3-amine hydrochloride (20 mg, 0.079 mmol) in saturated sodium bicarbonate solution (1.0 mL) and dioxane (1.0 mL) was added 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (31 mg, 0.079 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined extract was washed with water then brine solution (5 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by reverse phase HPLC to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-amine (15 mg, 37% yield). ¹H NMR (400 MHz, d₄-Methanol): 7.46-7.43 (dd, 1H), 7.35-7.33 (dd, 1H), 7.31-7.27 (m, 1H), 7.08-7.01 (dd, 1H), 6.63, 6.58 (td, 1H), 4.09-4.07 (d, 1H), 3.91-3.85 (dd, 2H), 3.76-3.73 (d, 1H), 2.80-2.74 (m, 1H), 2.73 (s, 2H), 1.07-1.05 (d, 6H); MS (EI) for C₂₀H₂₂F₃IN₄O: 519 (MH⁺).

Example 20 3-(1-amino-2-methylpropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

1,1-Dimethylethyl 3-oxoazetidine-1-carboxylate (677.2 mg, 3.96 mmol), prepared using procedures similar to those described in Example 3, was taken into 2-methyl-1-ntropropane (5 mL) then cooled to 0° C. followed by addition of potassium tert-butoxide (444 mg, 3.96 mmol) and the resulting mixture was allowed to warm to room temperature over 30 minutes. The mixture was partitioned with ethyl acetate and 0.5 N aqueous hydrochloric acid then once with water and brine then dried over anhydrous magnesium sulfate. Filtration and concentration afforded a residue (1.5 g) that was further purified by silica gel flash chromatography using 3:1 hexanes:ethyl acetate as eluent to give 1,1-dimethylethyl 3-hydroxy-3-(2-methyl-1-nitropropyl)azetidine-1-carboxylate (730 mg, 67% yield) as a colorless crystalline solid. ¹H-NMR (400 MHz, CDCl₃): 4.50 (d, 1H), 3.93 (dd AB, 2H), 3.85 (s, 2H), 3.58 (s, 1H), 2.54-2.48 (m, 1H), 1.44 (s, 9H), 1.04 (d, 6H).

1,1-Dimethylethyl 3-hydroxy-3-(2-methyl-1-nitropropyl)azetidine-1-carboxylate (105 mg, 0.38 mmol) was taken into methanol (1 mL) followed by addition of 4 N anhydrous hydrogen chloride in dioxane (1 mL) and the acidic solution was allowed to stand for 15 minutes at room temperature then concentrated and dried in vacuo to an amorphous residue. 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (150 mg, 0.38 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, was taken into DMF (0.7 mL) followed by addition of PyBOP (198 mg, 0.38 mmol) and the solution was allowed to stir for 10 minutes at room temperature. The above amine hydrochloride salt and DIPEA (190 μL, 1.1 mmol) in DMF solution (0.7 mL) was added and the mixture was allowed to stir for one hour at room temperature. The mixture was partitioned with ethyl acetate and 0.5 N aqueous hydrochloric acid and the organic phase washed three times with water then brine and dried over anhydrous magnesium sulfate. Filtration and concentration afforded a residue that was further purified by silica gel flash chromatography using 1.5:1 hexanes:ethyl acetate as eluent to give 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-methyl-1-nitropropyl)azetidin-3-ol (189 mg, 90% yield) as an amorphous solid. ¹H-NMR (400 MHz, CDCl₃): 8.41 (br s, 1H), 7.41 (dd, 1H), 7.34 (d, 1H), 7.09 (br m, 1H), 6.81 (q, 1H), 6.65-6.60 (m, 1H), 4.49 (d, 1H), 4.15-4.09 (m, 4H), 3.66 (s, 1H), 2.56-2.46 (m, 1H) 1.03 (d, 6H).

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-methyl-1-nitropropyl)azetidin-3-ol (189 mg, 0.34 mmol) was taken into 4:1 THF:water (5 mL) followed by addition of iron powder (192 mg, 3.4 mmol) and ammonium formate (429 mg, 6.8 mmol) and the mixture was heated to reflux. After four hours additional aliquots of iron powder (192 mg, 3.4 mmol) and ammonium formate (429 mg, 6.8 mmol) were added and the mixture was allowed to reflux an additional 12 hours. The mixture was cooled to room temperature and diluted with ethyl acetate then filtered. The filtrate was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate then the organic layer washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded a residue that was further purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents to give a residue (36.5 mg) that was further purified by preparative reverse phase HPLC to give 3-(1-amino-2-methylpropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol trifluoroacetate salt (7.9 mg) as a colorless amorphous solid after lyophillization of the combined pure fractions. ¹H-NMR (400 MHz, D₆-DMSO): 8.63 (s, 1H), 7.58 (dd, 1H), 7.37 (d, 1H), 7.35-7.31 (m, 1H), 7.17 (q, 1H), 6.71-6.66 (m, 1H), 4.23 (dd, 1H), 4.03 (dd, 1H), 3.80 (dd, 1H), 3.66 (dd, 1H), 2.34 (dd, 1H), 1.79-1.70 (m, 1H), 0.84-0.77 (m, 6H). MS (EI) for C₂₀H₂₁F₃IN₃O₂: 520 (MH⁺).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared:

Example 20(a)

3-(1-aminoethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1H), 7.91 (br s, 2H), 7.58 (d, 1H), 7.39 (d, 1H), 7.36-7.32 (m, 1H), 7.24-7.17 (m, 1H), 6.72-6.65 (m, 2H), 4.33-4.29 (m, 1H), 4.23-4.19 (m, 1H), 4.16-4.14 (m, 1H), 4.07-3.94 (m, 1H), 3.82-3.77 (m, 1H), 3.51-3.45 (m, 1H), 1.15-1.12 (m, 1H), 1.10-1.08 (m, 1H). MS (EI) for C₁₈H₁₇F₃IN₃O₂: 492 (MH⁺).

Example 20(b)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(ethylamino)ethyl]azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.61 (d, 1H), 8.50 (s, 1H), 8.20 (s, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.36-7.32 (m, 1H), 7.24-7.17 (m, 1H), 6.82 (s, 1H), 6.74-6.67 (m, 1H), 4.38 (d, 1H), 4.27 (d, 1H), 4.18 (d, 1H), 4.06 (d, 2H), 3.99 (d, 1H), 3.89 (d, 1H), 3.82 (d, 1H), 3.49-3.43 (m, 1H), 3.04-2.80 (m, 4H), 1.21-1.12 (m, 6H). MS (EI) for C₂₀H₂₁F₃IN₃O₂: 520 (MH⁺).

Example 20(c)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.57 (d, 1H), 7.58 (d, 1H), 7.38 (d, 1H), 7.37-7.33 (m, 1H), 7.22-7.17 (m, 1H), 6.73-6.66 (m, 1H), 6.57 (s, 1H), 5.06-4.97 (m, 1H), 4.54 (d, 0.5H), 4.37 (d, 0.5H), 4.29 (d, 0.5H), 4.14 (d, 0.5H), 4.05 (d, 0.5H), 3.95 (d, 0.5H), 3.86 (d, 0.5H), 3.80 (d, 0.5H), 1.44-1.38 (m, 3H). MS (EI) for C₁₈H₁₆F₃IN₃O₄: 523 (MH⁺).

Example 20(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(methylamino)ethyl]azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.63-8.55 (m, 1H), 8.44-8.23 (m, 1H), 7.79 (br s, 1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.36-7.31 (m, 1H), 7.24-7.17 (m, 1H), 6.82 (br s, 0.5H), 6.73-6.65 (m, 1H), 4.38-3.77 (m, 4H), 1.18-1.07 (m, 3H). MS (EI) for C₁₉H₁₉F₃IN₃O₂: 505 (M⁺).

Example 20(e)

methyl {1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate: ¹H NMR (400 MHz, d₆-DMSO): 8.59 (d, 1H), 7.58 (d, 1H), 7.41-7.05 (m, 4H), 6.72-6.64 (m, 1H), 5.84 (d, 1H), 4.20 (d, 0.5H), 4.08-4.04 (m, 1H), 3.92-3.85 (m, 1.5H), 3.76-3.71 (m, 1H), 3.69-3.63 (m, 1H), 3.46 (d, 2H), 0.99-0.95 (m, 3H). MS (EI) for C₂₀H₁₉F₃IN₃O₄: 550 (MH⁺).

Example 20(f)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(dimethylamino)ethyl]azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 9.45 (s, 1H), 8.61 (d, 1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.38-7.33 (m, 1H), 7.24-7.18 (m, 1H), 7.05 (s, 1H), 6.73-6.66 (m, 1H), 4.48 (d, 0.5H), 4.36 (d, 0.5H), 4.26 (d, 0.5H), 4.16-4.11 (m, 1H), 4.00-3.94 (m, 1H), 3.86 (d, 0.5H), 3.60-3.54 (m, 1H), 2.75-2.70 (m, 3H), 2.66-2.62 (br s, 3H), 1.22 (dd, 3H). MS (EI) for C₂₀H₂₁F₃IN₃O₂: 520 (MH⁺).

Example 20(g)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-nitropropyl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.46 (m, 1H), 7.35 (m, 1H), 7.28 (m, 1H), 7.07 (m, 1H), 6.61 (m, 1H), 4.65 (m, 1H), 4.44 (m, 1H), 4.25 (m, 1H), 4.02 (m, 1H), 3.86 (m, 1H), 2.04 (m, 1H), 1.76 (m, 1H), 0.94 (m, 3H). MS (EI) for C₁₉H₁₇F₃IN₃O₄: 536 (MH⁺).

Example 20(h)

3-(1-aminopropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.45 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.05 (m, 1H), 6.61 (m, 1H), 4.21 (m, 1H), 4.09-3.86 (m, 2H), 3.78 (m, 1H), 2.63 (m, 1H), 1.50 (m, 1H), 1.24 (m, 1H), 0.98 (m, 3H). MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 20(i)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(ethylamino)propyl]azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.45 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.05 (m, 1H), 6.61 (m, 1H), 4.23 (m, 1H), 4.02 (m, 1H), 3.90 (m, 1H), 3.79 (m, 1H), 2.70 (m, 1H), 2.54 (m, 1H), 1.53 (m, 1H), 1.40 (m, 1H), 1.05 (m, 3H), 0.95 (m, 3H). MS (EI) for C₂₁H₂₃F₃IN₃O₂: 534 (MH⁺).

Example 20(j)

3-[1-(diethylamino)propyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.44 (m, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 7.07 (m, 1H), 6.60 (m, 1H), 4.21 (m, 1H), 4.10 (m, 1H), 4.03-3.70 (m, 2H), 2.71-2.45 (m, 5H), 1.67 (m, 1H), 1.49 (m, 1H), 0.94 (m, 9H). MS (EI) for C₂₃H₂₇F₃IN₃O₂: 562 (MH⁺).

Example 20(k)

3-[amino(phenyl)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol): MS (EI) for C₂₃H₁₉F₃IN₃O₂: 554 (MH⁺).

Example 20(m)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(3-methyl-1-nitrobutyl)azetidin-3-ol): ¹H NMR (400 MHz, CDCl₃): 8.38 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.68 (dd, 1H), 4.23-4.04 (br m, 4H), 2.13 (t, 2H), 1.64-1.44 (br m, 3H), 0.93 (d, 6H); MS (EI) for C₂₁H₂₁F₃IN₃O₄: 564 (MH⁺).

Example 20(n)

3-(1-aminobutyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.38-7.33 (d, 1H), 7.32-7.26 (m, 1H), 7.09-7.00 (q, 1H), 6.66-6.58 (t, 1H), 4.33-4.22 (d, 1H), 4.13-3.81 (m, 3H), 3.17-3.09 (t, 1H), 1.93-1.89 (s, 3H), 1.89-1.82 (t, 3H), 1.56-1.24 (m, 4H), 0.97-0.88 (t, 3H); MS (EI) for C₂₀H₂₁F₃IN₃O₂: 520 (MH⁺).

Example 20(o)

3-(1-aminocyclopentyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CDCl₃): 8.27-8.21 (s, 1H), 7.42-7.36 (d, 1H), 7.34-7.29 (d, 1H), 7.15-7.09 (t, 1H), 7.09-7.01 (q, 1H), 6.88-6.79 (q, 1H), 6.63-6.53 (m, 1H), 4.18-3.92 (m, 4H), 2.12-2.08 (s, 3H), 2.06-1.70 (m, 7H), 0.92-0.68 (m, 4H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Example 20(p)

N-{1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}acetamide: ¹H NMR (400 MHz, CDCl₃): 8.42 (s, 1H), 7.41-7.38 (dd, 1H), 7.34-7.32 (dt, 1H), 7.12-7.09 (m, 1H), 6.85-6.78 (m, 1H), 6.63-6.57 (m, 1H), 5.76 (b, 1H), 4.28-3.98 (m, 5H), 2.00 (s, 3H), 1.20-1.19 (d, 3H); MS (EI) for C₂₀H₁₉F₃IN₃O₃: 534 (MH⁺).

Example 20(q)

(2R)—N-{1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanamide: ¹H NMR (400 MHz, CDCl3): 8.47 (s, 1H), 7.45-7.40 (m, 5H), 7.33-7.31 (m, 1H), 7.21-7.19 (m, 1H), 7.12-7.05 (m, 1H), 6.85-6.76 (m, 1H), 6.63-6.58 (m, 1H), 4.20-3.99 (m, 5H), 3.36 (s, 1.5H), 3.34 (s, 1.5H), 1.27-1.25 (d, 1.5H), 1.24-1.22 (d, 1.5H); MS (EI) for C₂₈H₂₄F₆IN₃O₄: 708 (MH⁺).

Example 20(r)

(2R)—N-{(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanamide: ¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.46-7.391 (m, 5H), 7.33-7.31 (m, 1H), 7.21-7.16 (m, 1H), 7.14-7.10 (m, 1H), 6.85-6.79 (m, 1H), 6.64-6.58 (m, 1H), 4.24-4.00 (m, 5H), 3.35 (s, 3H), 1.25-1.23 (d, 3H); MS (EI) for C₂₈H₂₄F₆IN₃O₄: 708 (MH⁺).

Example 20(s)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-methyl-1-nitroethyl)azetidin-3-ol: ¹H NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.41-7.38 (dd, 1H), 7.34-7.32 (dt, 1H), 7.14-7.10 (m, 1H), 6.87-6.81 (m, 1H), 6.64-6.59 (m, 1H), 4.33-4.15 (m, 4H), 1.64 (s, 6H); MS (EI) for C₁₉H₁₇F₃IN₃O₄: 536 (MH⁺).

Example 20(t)

3-(1-amino-1-methylethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.30 (s, 1H), 7.39-7.36 (dd, 1H), 7.32-7.30 (dt, 1H), 7.13-7.09 (m, 1H), 6.85-6.79 (m, 1H), 6.62-6.56 (m, 1H), 4.25-3.97 (m, 4H), 1.14 (s, 6H); MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 21 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1-[(trans-4-hydroxycyclohexyl)amino]ethyl}azetidin-3-ol hydrochloride

Potassium tert-butoxide (1.672 g, 14.9 mmol) and ethyltriphenylphosphonium bromide (5.538 g, 14.9 mmol) were stirred in ether (30 mL) at ambient for 1 h. 1,1-Dimethylethyl 3-oxoazetidine-1-carboxylate (954 mg, 6.0 mmol), prepared using procedures similar to those described in Example 3, was added and the mixture was 35° C. for 4.5 h. Mixture was filtered through celite and the solid was washed with ether. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ether in hexanes) gave 1,1-dimethylethyl 3-ethylideneazetidine-1-carboxylate (506 mg, 2.76 mmol, 49% yield): ¹H NMR (400 MHz, CDCl₃): 5.37-5.28 (m, 1H), 4.47-4.39 (m, 4H), 1.56-1.51 (m, 3H), 1.45 (s, 9H).

1,1-Dimethylethyl 3-ethylideneazetidine-1-carboxylate (506 mg, 2.76 mmol), and 4-methylmorpholine N-oxide (1.04 g, 8.89 mmol) were dissolved in acetone/water (4:1; 30 mL) and osmium tetroxide (2.5 wt. % in t-butanol; 0.2 mL) was added. The solution was stirred at ambient for 5 days, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave 1,1-dimethylethyl 3-hydroxy-3-(1-hydroxyethyl)azetidine-1-carboxylate (375 mg, 1.73 mmol, 63% yield): ¹H NMR (400 MHz, CDCl₃): 4.00-3.77 (m, 5H), 2.65 (br s, 1H), 1.86, (br s, 1H), 1.44 (s, 9H), 1.25 (d, 3H).

1,1-Dimethylethyl 3-hydroxy-3-(1-hydroxyethyl)azetidine-1-carboxylate (200 mg, 0.922 mmol) was dissolved in methanol (5 mL) and 4 N hydrochloric acid in dioxane (1 mL, 4 mmol) was added. The mixture was refluxed for 15 minutes and then was concentrated in vacuo to afford 3-(1-hydroxyethyl)azetidin-3-ol hydrochloride (0.922 mmol).

3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (362 mg, 0.921 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (337 mg, 2.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg, 1.11 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 5 minutes and then 3-(1-hydroxyethyl)azetidin-3-ol hydrochloride (0.922 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 80% ethyl acetate in hexanes) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-hydroxyethyl)azetidin-3-ol (296 mg, 0.602 mmol, 65% yield): MS (EI) for C₁₈H₁₆F₃IN₂O₃: 493 (MH⁺).

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-hydroxyethyl)azetidin-3-ol (267 mg, 0.543 mmol), was dissolved in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (80 mg, 0.661 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (183 mg, 0.604 mmol) at ambient for 15 h. Triethylamine (0.076 mL, 0.545 mmol) was added and the mixture was stirred at ambient for 3 h and then at 35° C. for 4 h and then at ambient for a further 15 h. 2,4,6-Triisopropylbenzenesulfonyl chloride (110 mg, 0.363 mmol) was added and the mixture was stirred at 35° C. for 3 h and then 4-(dimethylamino)pyridine (80 mg, 0.661 mmol) was added and the mixture was stirred at 35° C. for 2 h. 2,4,6-Triisopropylbenzenesulfonyl chloride (303 mg, 1.0 mmol) was added and the mixture was stirred at 35° C. for a further 18 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 30-50% ethyl acetate in hexanes) to give 1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (201 mg, 0.265 mmol, 49% yield): MS (EI) for C₃₃H₃₈F₃IN₂O₅S: 759 (MH⁺).

1-[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (194 mg, 0.256 mmol) was dissolved in tetrahydrofuran (2 mL) and was cooled to 0° C. Sodium hydride (60 wt % dispersion in oil; 31 mg, 0.775 mmol) was added and the mixture was stirred at 0° C. for 15 minutes. The mixture was quenched with saturated sodium bicarbonate solution and partitioned with ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(2-methyl-1-oxa-5-azaspiro[2.3]hex-5-yl)carbonyl]aniline (120 mg, 0.253 mmol, 99% yield): MS (EI) for C₁₈H₁₄F₃IN₂O₂: 475 (MH⁺).

2,3-Difluoro-N-(2-fluoro-4-iodophenyl)-6-[(2-methyl-1-oxa-5-azaspiro[2.3]hex-5-yl)carbonyl]aniline (50 mg, 0.105 mmol) was dissolved in dimethylsulfoxide (0.8 mL) and treated with trans-4-cyclohexanolamine (70 mg, 0.609 mmol) with 100 W microwave power at 100° C. for 45 minutes. The mixture was purified by reverse phase HPLC and the clean fractions were combined, neutralized with saturated sodium bicarbonate solution and the organic solvent was removed in vacuo. The remaining aqueous residue was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was treated with aqueous hydrochloric acid and then was lyophilized to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1-[(trans-4-hydroxycyclohexyl)amino]ethyl}azetidin-3-ol hydrochloride (36 mg, 0.058 mmol, 55% yield): ¹H NMR (400 MHz, d₆-DMSO): 8.61 (br s, 0.5H), 8.55 (br s, 0.5H), 8.49-8.33 (m, 1H), 8.08-7.90 (m, 1H), 7.59 (dd, 1H), 7.39 (br d, 1H), 7.37-7.30 (m, 1H), 7.21 (br q, 1H), 6.81 (br d, 1H), 6.77-6.65 (m, 1H), 4.20 (br d, 1H), 4.09-4.02 (m, 1H), 3.97 (br d, 1H), 3.93-3.80 (m, 1H), 3.62-3.47 (m, 1H), 3.03-2.90 (m, 1H), 2.07-1.93 (m, 2H), 1.93-1.77 (m, 2H), 1.54-1.06 (m, 8H); MS (EI) for C₂₄H₂₇F₃IN₃O₃: 590 (MH⁺).

Example 21(a)

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compound of the invention was prepared: 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1-[(1,1-dimethylethyl)amino]ethyl}azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.63 (br s, 0.4H), 8.53 (br s, 0.6H), 7.56 (dt, 1H), 7.40-7.34 (m, 1H), 7.32-7.26 (m, 1H), 7.25-7.13 (m, 1H), 6.72-6.62 (m, 1H), 5.43 (br s, 1H), 4.14-3.56 (m, 4H), 2.69-2.53 (m, 1H), 1.00-0.85 (br, 12H); MS (EI) for C₂₂H₂₅F₃IN₃O₂: 548 (MH⁺).

Example 22(a) and 22(b) 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol

and 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol

To a solution of 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (368 mg, 0.94 mmol), prepared using procedures similar to those described in Reference 5, in dichloromethane (5 mL) was added DMAP (115 mg, 0.94 mmol) and the resulting solution was cooled to 0° C. (R)-(−)-α-Methoxy-α-trifluoromethylphenylacetyl chloride (105 μL, 0.56 mmol) was added to the solution by syringe and the mixture was allowed to warm to room temperature then stirred an additional 12 hours. The solution was then partitioned with saturated aqueous sodium bicarbonate and the organic phase dried over anhydrous magnesium sulfate then filtered and concentrated to an oily residue. Silica gel flash chromatography using hexanes:ethyl acetate 3:1 as eluent afforded the less polar 1,1-dimethylethyl (2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (27.5 mg, 5% yield), the more polar 1,1-dimethylethyl (2S)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (105 mg, 19% yield) and starting material (253 mg, 69% recovery).

The starting material thus recovered was taken into dichloromethane (3 mL) followed by addition of DMAP (115 mg, 0.94 mmol) and (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (105 μL, 0.56 mmol) and the mixture was allowed to stir at room temperature over 12 hours. Proceeding as before afforded combined 1,1-dimethylethyl (2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (46.6 mg, 8% yield), the more polar 1,1-dimethylethyl (2S)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (228 mg, 41% yield) and starting material (100.8 mg, 27% recovery).

The starting material thus recovered was taken into tetrahydrofuran:dichloromethane (1:1, 2 mL) followed by addition of DMAP (47 mg, 0.39 mmol) and (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (80 μL, 0.43 mmol) and the mixture was heated to 60° C. over 12 hours. Proceeding as before afforded combined less polar 1,1-dimethylethyl (2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (144 mg, 26% yield). The chiral ester derivatives thus obtained were again subject to silica gel flash chromatography using hexanes:ethyl acetate 3:1 as eluent to give the pure less polar 1,1-dimethylethyl (2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (122.8 mg, 22% yield) and the more polar 1,1-dimethylethyl (2S)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (177.6 mg, 32% yield) both as colorless amorphous residues.

1,1-Dimethylethyl (2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (122.8 mg, 0.21 mmol) was taken into methanol (4 mL) followed by addition of 1M aqueous sodium hydroxide (1 mL) and the resulting solution was stirred for one hour at room temperature. The solution was then partitioned with ethyl acetate and 1N aqueous hydrochloric acid. The organic layer was washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. The residue was purified by silica gel flash chromatography using hexanes:ethyl acetate 2:1 to give 1,1-dimethylethyl (2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (60.8 mg, 81% yield) a colorless amorphous solid. 1,1-dimethylethyl (2S)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (87.4 mg, 75% yield) was prepared analogously.

1,1-Dimethylethyl (2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (60.8 mg, 0.16 mmol) and 10% Pd/C (30 mg) were taken into methanol (2 mL) and the mixture hydrogenated at ambient pressure for one hour. The suspension was then filtered through a celite pad and concentrated then dried in vacuo to a colorless solid. The solid amine was taken into THF (1 mL) followed by addition of DIPEA (42 μL, 0.24 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (63 mg, 0.16 mmol), prepared using procedures similar to those described in Reference 1, and the mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and 1 N aqueous hydrochloric acid and the organic layer washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using hexanes:ethyl acetate 3:2 as eluent afforded 1,1-dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 74% yield) as an amorphous solid. 1,1-Dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate ¹H NMR (400 MHz, CDCl₃): 8.53 (br s, 0.5H), 8.40 (br s, 0.5H), 7.41-7.38 (dd, 1H), 7.34-7.31 (dt, 1H), 7.17-7.14 (m, 1H), 6.86-6.79 (m, 1H), 6.63-6.587 (m, 1H), 4.24-3.90 (m, 4H), 3.37-3.23 (m, 1H), 2.90-2.80 (m, 1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (EI) for C₂₆H₂₉F₃IN₃O₄: 576 (M-C₄H₉ ⁺).

1,1-dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 0.12 mmol) was taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane (1 mL) and the solution was stirred at room temperature for one hour. The solution was then concentrated and the residue partitioned with chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using ethyl acetate then concentrated aqueous ammonia in chloroform and methanol (0.1:10:1) as eluents afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol (57.3 mg) as a colorless amorphous solid. The free base was taken into methanol (1 mL) then brought to about pH 1 by addition of 4 N HCl in dioxane and the solution concentrated. The residue was triturated with ethyl ether to afford a suspension. The solid was collected by filtration to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol hydrochloride salt (49 mg, 72% yield) as a colorless solid. ¹H NMR (400 MHz, CDCl₃): 8.43-8.39 (d, 1H), 7.41-7.38 (dd, 1H), 7.33-7.31 (dt, 1H), 7.14-7.10 (m, 1H), 6.84-6.80 (m, 1H), 6.63-6.57 (m, 1H), 4.12-3.99 (m, 4H), 3.10-3.08 (d, 1H), 2.72-2.69 (d, 1H), 2.64-2.62 (m, 1H), 1.61-1.58 (m, 2H), 1.36-1.16 (m, 4H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared:

Example 22(c)

1,1-dimethylethyl (2S)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate: ¹H NMR (400 MHz, CDCl₃): 8.52 (br s, 0.5H), 8.39 (br s, 0.5H), 7.41-7.38 (dd, 1H), 7.34-7.31 (dt, 1H), 7.17-7.12 (m, 1H), 6.85-6.79 (m, 1H), 6.63-6.57 (m, 1H), 4.25-3.88 (m, 4H), 3.34-3.26 (m, 1H), 2.80-2.90 (m, 1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (EI) for C₂₆H₂₉F₃IN₃O₄: 576 (M-C₄H₉ ⁺).

Example 22(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol hydrochloride: ¹H NMR (400 MHz, d₄-Methanol): 7.49-7.46 (dd, 1H), 7.37-7.35 (dt, 1H), 7.35-7.30 (m, 1H), 7.10-7.04 (m, 1H), 6.64-6.59 (m, 1H), 4.39-4.32 (dd, 1H), 4.21-4.18 (dd, 1H), 4.13-4.07 (m, 1H), 3.97-3.88 (dd, 1H), 3.57-3.32 (m, 1H), 3.02-2.96 (dd, 1H), 1.90-1.50 (m, 7H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Example 22(e)

1-({2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorophenyl}carbonyl)-3-piperidin-2-ylazetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.56 (d, 1H), 7.29-7.38 (m, 2H), 7.08-7.16 (m, 1H), 6.64-6.70 (m, 1H), 4.30-4.40 (m, 1H), 4.18-4.26 (m, 1H), 4.04-4.14 (m, 1H), 3.90-4.00 (m, 1H), 3.16-3.26 (m, 2H), 2.86-2.96 (m, 1H), 1.91 (s, 3H), 1.76-1.88 (m, 3H), 1.44-1.64 (m, 3H). MS (EI) for C₂₁H₂₁BrClF₂N₃O₂: 500 (M-H).

Example 22(f)

1-({2-[(4-bromo-2-fluorophenyl)amino]-3,4-difluorophenyl}carbonyl)-3-piperidin-2-ylazetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 8.52 (br s, 1H), 7.50 (d, 1H), 7.35-7.15 (m, 3H), 6.88-6.79 (m, 1H), 4.15-3.96 (m, 1H), 3.84-3.78 (m, 1H), 3.68-3.63 (m, 1H), 2.95-2.88 (m, 1H), 2.48-2.40 (m, 2H), 1.71-1.42 (m, 3H), 1.25-1.14 (m, 2H), 1.03-0.90 (m, 1H); MS (EI) for C₂₁H₂₁BrF₃N₃O₂: 485 (MH⁺).

Example 22(g)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.45 (dd, 1H), 7.37-7.31 (m, 1H), 7.30-7.25 (m, 1H), 7.13-6.99 (m, 1H), 6.67-6.54 (m, 1H), 4.20-4.09 (m, 1H), 4.08-3.91 (m, 2H), 3.88-3.79 (m, 1H), 3.27 (t, 1H), 2.99-2.89 (m, 1H), 2.88-2.81 (m, 1H), 1.93-1.67 (m, 3H), 1.55-1.42 (m, 1H). MS (EI) for C₂₀H₁₉F₃IN₃O₂: 518 (MH⁺)

Example 22(h)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-methylpyrrolidin-2-yl)azetidin-3-ol acetate (salt): ¹H NMR (400 MHz, CD₃OD): 7.46 (dd, 1H), 7.38-7.26 (m, 2H), 7.12-6.99 (m, 1H), 6.66-6.56 (m, 1H), 4.37-3.87 (m, 4H), 2.94-2.82 (m, 1H), 2.75-2.63 (m, 3H), 2.20-2.06 (m, 1H), 2.00-1.67 (m, 8H). MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Example 22(i)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-ethylpyrrolidin-2-yl)azetidin-3-ol acetate (salt): ¹H NMR (400 MHz, CD₃OD): 7.46 (d, 1H), 7.38-7.33 (m, 1H), 7.32-7.27 (m, 1H), 7.12-7.01 (m, 1H), 6.66-6.57 (m, 1H), 4.34-3.89 (m, 4H), 3.57 (t, 1H), 3.51-3.40 (m, 1H), 3.28-2.81 (m, 3H), 2.25-1.72 (m, 8H), 1.31-1.18 (m, 3H). MS (EI) for C₂₂H₂₃F₃IN₃O₂: 546 (MH⁺).

Example 22(j)

1-({4-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol acetate salt: ¹H NMR (400 MHz, d₄-MeOH): 8.30 (s, 1H), 7.56 (s, 1H), 7.42 (d, 1H), 7.24 (d, 1H), 6.34 (m, 1H), 4.20 (d, 2H), 3.92 (s, 3H), 3.38-3.24 (m, 3H), 3.08 (bs, 1H), 2.88 (bs (1H), 1.90-1.70 (m, 3H), 1.66-1.32 (m, 3H); MS (EI) for C₂₃H₂₄F₂IN₅O₂: 568 (MH⁺).

Example 22(k)

1-({7-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol acetate salt: ¹H NMR (400 MHz, d₄-MeOH): 8.22 (s, 1H), 7.60 (s, 1H), 7.42 (d, 1H), 7.26 (d, 1H), 6.46 (m, 1H), 4.21 (d, 2H), 4.06 (s, 3H), 3.88 (m, 1H), 3.38-3.24 (m, 3H), 3.10 (bs, 1H), 2.88 (bs (1H), 1.88-1.70 (m, 3H), 1.64-1.28 (m, 3H); MS (EI) for C₂₃H₂₄F₂IN₅O₂: 568 (MH⁺).

Example 22(m)

4-[(4-bromo-2-fluorophenyl)amino]-3-fluoro-5-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-1-methylpyridin-2(1H)-one: MS (EI) for C₂₁H₂₃BrF₂N₄O₃: 498 (MH⁺).

Example 22(n)

1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol: ¹H NMR (400 MHz, d₆-DMSO): 8.79 (s, 1H), 8.04 (d, 1H), 7.91 (d, 1H), 7.64 (dd, 1H), 7.55 (d, 1H), 6.95-7.02 (m, 1H), 4.38 (d, 1H), 4.15 (dd, 1H), 3.99 (dd, 1H), 3.72 (q, 1H), 3.32-3.39 (m, 1H), 3.00-3.12 (m, 1H), 1.93 (t, 3H), 1.51-1.70 (m, 3H); MS (EI) for C₂₂H₂₂ClFIN₅O₂: 532 (MH⁺).

Example 22(o)

1-({7-[(4-bromo-2-chlorophenyl)amino]-8-chloroimidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol: ¹H NMR (400 MHz, d₄-MeOH): 8.85 (s, 1H), 8.06 (d, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.45 (d, 1H), 7.01 (d, 1H), 4.48 (d, 1H), 4.10-4.27 (m, 2H), 3.87 (q, 1H), 3.37 (d, 2H), 3.02 (s, 1H), 1.88-1.94 (m, 3H), 1.58-1.69 (m, 3H); C₂₂H₂₂BrCl₂N₅O₂: 540 (MH⁺).

Example 22(p)

1-({6-[(4-bromo-2-chlorophenyl)amino]-7-fluoro-3-methyl-1,2-benzisoxazol-5-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 8.50 (m, 1H), 7.51 (d, 1H), 7.42 (s, 1H), 7.26 (dd, 1H), 6.79 (dd, 1H), 4.20-3.98 (br m, 4H), 3.11 (d, 1H), 2.77-2.50 (br m, 5H), 1.80-1.15 (br m, 6H); MS (EI) for C₂₃H₂₃BrClFN₄O₃: 537 (MH⁺).

Example 22(q)

1-({3-fluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol: ¹H NMR (400 MHz, d₄-MeOH): 7.53 (2d, 1H), 7.46 (m, 2H), 7.16 (t, 1H), 6.86 (m, 1H), 6.63 (m, 1H), 4.36 (m, 1H), 4.22 (m, 1H), 4.02 (m, 1H), 3.88 (m, 1H), 3.08 (d, 1H), 2.66 (dd, 1H), 2.56 (m, 1H), 1.82 (bs, 1H), 1.66 (d, 1H), 1.58 (d, 1H), 1.38 (m, 2H), 1.22 (m, 1H); MS (EI) for C₂₁H₂₂F₂IN₃O₂: 514 (MH⁺).

Example 22(r)

1-({4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol: ¹H NMR (400 MHz, d₄-MeOH): 7.42 (2d, 1H), 7.34-7.18 (m, 4H), 6.46 (m, 1H), 4.10 (m, 2H), 3.84 (m, 2H), 3.04 (d, 1H), 2.52 (dd, 2H), 1.76 (bs, 0.5H), 1.58 (m, 2.5H), 1.32 (m, 2H), 1.18 (m, 0.5H), 1.04 (m, 0.5H); MS (EI) for C₂₁H₂₂F₂IN₃O₂: 514 (MH⁺).

Example 22(s)

5-[(2-fluoro-4-iodophenyl)amino]-6-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-2-methylpyridazin-3(2H)-one: ¹H NMR (400 MHz, d₆-DMSO): 10.19 (s, 1H), 7.78 (dd, 1H), 7.59 (d, 1H), 7.32 (t, 1H), 5.95 (s, 1H), 4.59 (q, 1H), 4.13-4.27 (m, 2H), 3.77 (d, 1H), 3.62 (s, 3H), 3.02 (d, 2H), 2.71 (d, 1H), 1.78 (s, 1H), 1.68 (d, 1H), 1.53 (d, 1H), 1.32 (s, 2H), 1.17 (t, 1H); MS (EI) for C₂₀H₂₃FIN₅O₃: 528 (MH+).

Example 23 1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-3-nitroguanidine hydrochloride

To a mixture of 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-(1-oxa-5-azaspiro[2,3]hex-5-ylcarbonyl)aniline (0.15 g, 0.33 mmol), prepared using procedures similar to those described in Example 21, and nitroguanidine (0.1 g, 1.00 mmol) in tetrahydrofuran (3.00 mL) an aqueous solution of sodium hydroxide (1.0 mL, 2.0 mmol) was added and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. The fractions were collected, and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was dissolved in methanol, and 4 N HCl in dioxane (80 μL, 0.33 mmol) was added to the solution. A white precipitate formed and was collected by filtration. The solid was washed with hexane, and dried to afford 76 mg (38%) 1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-3-nitroguanidine hydrochloride. ¹H NMR (400 MHz, d₄-MeOH): 7.46 (2d, 1H), 7.36 (m, 1H), 7.29 (m, 1H), 7.02 (m, 1H), 6.63 (m, 1H), 4.22 (m, 1H), 4.01 (m, 2H), 3.86 (m, 1H), 3.51 (d, 2H); MS (EI) for C₁₈H₁₆F₃IN₆O₄: 565 (MH⁺).

Example 23(a)

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: 1-cyano-3-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}guanidine hydrochloride. ¹H NMR (400 MHz, d₄-MeOH): 7.47 (2d, 1H), 7.36 (m, 1H), 7.27 (m, 1H), 7.03 (m, 1H), 6.63 (m, 1H), 4.18 (m, 1H), 3.98 (m, 2H), 3.80 (m, 1H), 3.43 (s, 2H); MS (EI) for C₁₉H₁₆F₃IN₆O₂: 545 (MH⁺).

Example 24 6-({3-[(ethylamino)methyl]-3-fluoroazetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline

To 1,1-dimethylethyl [{1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}ethylcarbamate (27 mg, 0.044 mmol), prepared using procedures similar to those in Example 3 and followed by Boc-protection, in chloroform (2.5 mL) added DAST (11.8 μL, 0.089 mmol) and stirred for 3.5 hr at room temperature. Quenched with water (15 mL), partitioned phases and extracted aqueous phase with chloroform (2×15 mL). The combined chloroform extracts were dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified on a silica gel column to afford 1,1-dimethylethyl [{1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-fluoroazetidin-3-yl]methyl}ethylcarbamate (19.0 mg, 70%).

To the 1,1-dimethylethyl [{1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-fluoroazetidin-3-yl]methyl}ethylcarbamate (19.0 mg, 0.031 mmol) in acetonitrile (1.0 mL) added a solution 4.0N hydrogen chloride in dioxane (1.0 mL). After 1.5 hr the solution was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to afford the title compound (4.30 mg, 27%). ¹H NMR (400 MHz, CDCl₃): 8.25 (s, 1H), 7.33 (dd, 1H), 7.33-7.25 (m, 1H), 7.18-7.14 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.33-4.05 (br m, 4H), 3.07-2.95 (br m, 2H), 2.65 (q, 2H), 1.08 (t, 3H); MS (EI) for C₁₉H₁₈F₄IN₃O: 508 (MH⁺).

Example 25 3-(2-aminocyclohexyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

A solution of 1-(trimethylsiloxy)cyclohexene (200 mg, 1.17 mmol) and benzyl 3-oxoazetidine-1-carboxylate (289 mg, 1.41 mmol), prepared using procedures similar to those described in Reference 3, in tetrahydrofuran (3.90 mL) was cooled to −78° C. for 10 minutes followed by the addition of titanium tetrachloride (0.13 mL, 1.17 mmol). The reaction mixture stirred for an additional 5 hours at −78° C. The mixture was quenched with aqueous sodium bicarbonate and the aqueous layer was extracted with ether (2×). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified on silica gel chromatography column (3:2 hexanes/ethyl acetate) to afford benzyl 3-hydroxy-3-(2-oxocyclohexyl)azetidine-1-carboxylate (328 mg, 37%). ¹H NMR (CDCl₃): 7.28-7.34 (m, 5H), 5.08 (s, 2H), 4.02 (d, 1H), 3.89 (d, 1H), 3.87 (s, 1H), 3.55 (s, 1H), 2.71 (q, 1H), 2.29-2.43 (m, 2H), 2.11 (s, 2H), 1.95 (s, 1H), 1.66 (d, 3H); MS (EI) for C₁₇H₂₁NO₄: 303 (MH+).

A solution of benzyl 3-hydroxy-3-(2-oxocyclohexyl)azetidine-1-carboxylate (100 mg, 330 mmol) in methanol (1.60 mL) in the presence of ammonium acetate (191 mg, 2.48 mmol was cooled to 0° C. for 1 hour. Sodium cyanoborohydride (81.5 mg, 1.30 mmol) was added and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 6 N hydrogen chloride (800 μL) and extracted with ethyl acetate. The aqueous layer was basified with aqueous sodium bicarbonate (pH 9) and extracted with dichloromethane. The combined organic portion was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford benzyl-3-(2-aminocyclohexyl)-3-hydroxyazetidine-1-carboxylate (73.7 mg, 73%). MS (EI) for C₁₇H₂₄N₂O₃: 305 (MH⁺).

To a solution of benzyl-3-(2-aminocyclohexyl)-3-hydroxyazetidine-1-carboxylate (202 mg, 0.663 mmol) in dioxane-water (1:1, 2.5 mL) was added di-tert-butyl dicarbonate (138 mg, 0.630 mmol) and solid sodium bicarbonate (112 mg, 1.33 mmol). The reaction mixture was stirred at room temperature for 2 hours and evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford benzyl 3-(2-tert-butoxycarbonylamino)cyclohexyl)-3-hydroxyazetidine-1-carboxylate (237 mg, 100%). ¹H NMR (CH₃OH): 7.15-7.21 (m, 5H), 5.45 (s, 0.5H), 5.20 (d, 0.5H), 4.95 (s, 2H), 4.81 (s, 1H), 3.81 (d, 2H), 1.43-1.74 (m, 5H), 1.39 (s, 1H), 1.31 (s, 1H), 1.20 (s, 1H). MS (EI) for C₂₂H₃₂N₂O₅: 405 (MH+).

A solution of benzyl 3-(2-tert-butoxycarbonylamino)cyclohexyl)-3-hydroxyazetidine-1-carboxylate (237 mg, 0.586 mmol) in ethyl acetate (2 mL) was hydrogenated over 10% palladium-carbon (200 mg, 0.586 mmol) at 40 psi for 16 hours. The reaction mixture was filtered and concentrated in vacuo to provide tert-butyl 2-(3-hydroxyazetidin-3-yl)cyclohexylcarbamate (181 mg, 100%). ¹H NMR (CDCl₃): 5.10 (s, 1H), 4.80 ((s, 1H), 3.78-3.86 (m, 1H), 3.61 (d, 1H), 3.57 (s, 1H), 3.36 (d, 1H), 1.77 (s, 2H), 1.40-1.53 (m, 1H), 1.36 (d, 9H), 1.25 (s, 2H). MS (EI) for C₁₄H₂₆N₂O₃: 271 (MH+).

To a solution of tert-butyl 2-(3-hydroxyazetidin-3-yl)cyclohexylcarbamate (181 mg, 0.669 mmol) and 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl fluoride (265 mg, 0.669 mmol), prepared using procedures similar to those described in Reference 1, in tetrahydrofuran (2.2 mL) was added N,N-diisopropylethylamine (110 μL) at room temperature. After an hour, the reaction mixture was heated to 50° C. and stirred for 45 minutes, at which time it was cooled to room temperature and evaporated. The residue was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl-2-(1-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl)-3-hydroxyazetidin-3-yl)cyclohexylcarbamate. This crude material was taken into the next step without further purification.

Tert-butyl-2-(1-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl)-3-hydroxyazetidin-3-yl)cyclohexylcarbamate was dissolved in a mixture of methanol (4 mL) and hydrogen chloride (4 M in dioxane) (3 mL). The solution was heated to reflux then cooled to room temperature and stirred for 16 hours. The reaction mixture was concentrated and purified by reverse phase HPLC. The purified fractions were evaporated to dryness and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford an oil. The residue was taken up in methanol (2 mL) and was added hydrogen chloride (4M in dioxane) (700 μL) and evaporated to dryness to afford the title compound 3-(2-aminocyclohexyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol hydrochloride (44.7 mg, 12%).

¹H NMR (400 MHz, d₆-DMSO): 8.58 (d, 1H), 7.59 (dd, 1H), 7.54 (s, 2H), 7.38 (d, 1H), 7.33 (t, 1H), 7.16-7.25 (m, 1H), 6.69 (dt, 1H), 6.41 (s, 1H), 4.26 (d, 0.5H), 4.17 (d, 0.5H), 4.04 (t, 1H), 3.90 (t, 1H), 3.79 (d, 0.5H), 3.65-3.73 (m, 0.5H), 3.45-3.51 (m, 1H), 1.88 (s, 1H), 1.65-1.88 (m, 2H), 1.47 (s, 4H), 1.16-1.37 (m, 2H); MS (EI) for C₂₂H₂₃F₃IN₃O₂: 546 (MH⁺).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared:

Example 25(c)

3-(2-aminocyclopentyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; ¹H NMR (400 MHz, d₆-DMSO): 8.56 (d, 1H), 7.82 (d, 1H), 7.59 (td, 1H), 7.45 (s, 1H), 7.38 (d, 1H), 7.30-7.35 (m, 1H), 7.18-7.24 (m, 1H), 6.68-6.72 (m, 1H), 6.41 (s, 0.5H), 6.17 (s, 0.5H), 3.91-4.27 (m, 2.5H), 3.78-3.86 (m, 1H), 3.65-3.73 (m, 1H), 3.44-3.52 (m, 0.5H), 2.19-2.26 (m, 1H), 1.54-1.94 (m, 5H), 1.30-1.39 (m, 1H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Example 25(a) and Example 25(b) (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(trans)-2-hydroxycyclohexyl]azetidin-3-ol and (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(cis)-2-hydroxycyclohexyl]azetidin-3-ol

The compounds of examples 25a and 25b were synthesized starting from benzyl 3-hydroxy-3-(2-oxycyclohenyl)azetidine-1-carboxylate prepared according to the procedure given in example 25. The ketone was reduced to give benzyl 3-hydroxy-3-(2-hydroxycyclohexyl)azetidine-1-carboxylate as a mixture of racemic diastereomers which were subjected to hydrogenation to afford 3-(2-hydroxycyclohexyl)azetidin-3-ol. 3-(2-hydroxycyclohexyl)azetidin-3-ol was then carried forward in a coupling step with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl fluoride in the usual manner. The coupled material thus obtained was purified by preparative reverse phase HPLC where fraction 1 was tentatively assigned as (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(trans)-2-hydroxycyclohexyl]azetidin-3-ol (Example 25a) and fraction 2 was tentatively assigned as (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(cis)-2-hydroxycyclohexyl]azetidin-3-ol.

Example 25(a)

First eluting fraction: ¹H NMR (400 MHz, d₄-MeOH): 7.44 (2d, 1H), 7.34 (t, 1H), 7.25 (m, 1H), 7.03 (m, 1H), 6.60 (m, 1H), 4.46 (d, 0.5H), 4.28 (d, 0.5H), 4.22 (d, 0.5H), 3.98 (dd, 1H), 3.89 (d, 0.5H), 3.85 (s, 0.5H), 3.77 (d, 0.5H), 3.56 (m, 1H), 1.90 (m, 1H), 1.46-1.74 (m, 4H), 0.98-1.32 (m, 4H); MS (EI) for C₂₂H₂₂F₃IN₂O₃: 547 (MH⁺).

Example 25(b)

Second eluting fraction: ¹H NMR (400 MHz, d₄-MeOH): 7.44 (2d, 1H), 7.33 (d, 1H), 7.26 (m, 1H), 7.04 (m, 1H), 6.59 (dd, 1H), 4.20 (m, 1.5H), 4.19 (s, 0.5H), 4.00 (m, 1.5H), 3.86 (dd, 1H), 3.74 (d, 0.5H), 1.76 (m, 2H), 1.50-1.68 (m, 5H), 1.18-1.46 (m, 4H); MS (EI) for C₂₂H₂₂F₃IN₂O₃: 547 (MH⁺).

Example 26 3-({[(E)-1-amino-2-nitroethenyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

A solution of 3-(aminomethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (0.24 g, 0.5 mmol), prepared using procedures similar to those described in Example 3, and commercially available 1,1-bis(methylthio)-2-nitroethylene (0.083 g, 0.5 mmol) in ethanol (5 mL) was stirred at 70° C. for 16 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford 0.10 g, (39%) 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(Z)-1-(methylthio)-2-nitroethenyl]amino}methyl)azetidin-3-ol. MS (EI) for C₂₀H₁₈F₃IN₄O₄S: 595 (MH⁺).

To a solution of (0.05 g 0.08 mmol) 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(Z)-1-(methylthio)-2-nitroethenyl]amino}methyl)azetidin-3-ol in ethanol (2 mL) was added ammonium hydroxide (0.1 mL, 0.8 mmol) and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. The fractions were collected and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was dissolved in methanol, and 4 N HCl in dioxane (40 μL, 0.16 mmol) was added to the solution. A white precipitate formed and was collected by vacuum filtration. The solid was washed with hexane, and dried to afford 42 mg (87%) 3-({[(E)-1-amino-2-nitroethenyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol hydrochloride. ¹H NMR (400 MHz, d₄-MeOH): 7.58 (t, 0.5H), 7.44 (t, 0.5H), 7.36 (m, 1H), 7.31 (m, 1H), 7.04 (m, 1H), 6.63 (m, 1H), 3.90-4.30 (m, 4H) 3.72 (s, 2H); MS (EI) for C₁₉H₁₇F₃IN₅O₄: 564 (MH⁺).

Example 27 1-({3,4-difluoro-2-[((2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-2-ylmethyl)azetidin-3-ol

A solution of 2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.5 g, 2.3 mmol) (prepared using procedures similar to those described in Clader et. al. J. of Med. Chem. 1995, 38(10), 1600-7) in tetrahydrofuran (5 mL) was cooled to −78° C., and n-butyllithium was added (2.5 M in hexanes, 0.990 mL, 2.5 mmol). After 2 hours, 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (0.60 g, 3.5 mmol), prepared using procedures similar to those described in Example 3, in 2.0 mL tetrahydrofuran was added and the solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with an excess of saturated aqueous ammonium chloride solution and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.37 g (41%) of 3-{[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-2-yl]methyl}azetidin-3-ol: ¹H NMR (400 MHz, CDCl₃): 6.96-6.92 (m, 1H), 5.23 (s, 2H), 3.98 (d, 2H), 3.79 (d, 2H), 3.52-3.47 (m, 2H), 3.13 (s, 2H), 1.43 (s, 9H), 0.94-0.88 (m, 2H), 0.00 (s, 9H).

3-{[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-2-yl]methyl}azetidin-3-ol (0.19 g, 0.49 mmol) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature overnight and the solvent was removed under vacuum to give 0.16 g of 3-(1H-imidazol-2-ylmethyl)azetidin-3-ol trifluoroacetate salt (87%). The crude residue was used without further purification for the next step.

To a solution of 3-(1H-imidazol-2-ylmethyl)azetidin-3-ol trifluoroacetate salt (0.16 g, 0.42 mmol) and N,N-diisopropylethylamine (0.370 mL, 2.13 mmol) in tetrahydrofuran (2.0 mL) 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (0.17 g, 0.42 mmol), prepared using procedures similar to those described in Reference 1, was added and the reaction mixture was stirred for 3 hours at room temperature. The solution was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by reverse-phase HPLC followed by lyophilization of the pure fractions gave 0.032 g (13%) of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-2-ylmethyl)azetidin-3-ol acetate salt: ¹H NMR (400 MHz, CD₃OD): 7.45 (dd, 1H), 7.38-7.33 (m, 1H), 7.25-7.18 (m, 1H), 7.08-6.96 (m, 1H), 6.89 (s, 2H), 6.65-6.56 (m, 1H), 4.33-4.22 (m, 1H), 4.17-4.00 (m, 2H), 3.91-3.80 (m, 1H), 3.08 (s, 2H), 1.96 (s, 3H). MS (EI) for C₂₀H₁₆F₃IN₄O₂: 529 (MH⁺).

Example 28 3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

To a solution of diisopropylamine (6.5 mL, 46.3 mmol) in THF (200 mL) at −78° C. was added butyllithium (17 mL of a 2.5 M solution in hexanes, 42.5 mmol) over 5 min. The solution of lithium diisopropylamide was stirred for 15 min at −78° C. A solution of (S)-4-benzyl-3-propionyl-2-oxazolidinone (9.0 g, 38.6 mmol) in THF (100 mL) was added to the lithium diisopropylamide by addition funnel over 26 min. The reaction temperature was kept below −70° C. during the course of the addition. After the addition, the mixture was stirred for a further 30 min at −78° C. Then phenylmethyl 3-oxoazetidine-1-carboxylate (9.5 g, 46.3 mmol) was added by addition funnel over 25 minutes as a solution in THF (100 mL). Again, the reaction mixture was kept below −70° C. during the reagent addition. After stirring for an additional 1 hour at −78° C., the reaction mixture was quenched with saturated ammonium chloride solution and was then allowed to warm to rt. Water was added to dissolve any precipitated ammonium chloride, and ethyl acetate was added. The layers were partitioned, and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (50% ethyl acetate: 50% hexanes) to provide phenylmethyl 3-hydroxy-3-{(1R)-1-methyl-2-oxo-2-[(4S)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]ethyl}azetidine-1-carboxylate as a white crystalline solid (6.03 g, 13.8 mmol, 36% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.37 (m, 8H), 7.20 (d, 2H), 5.12 (s, 2H), 4.66 (m, 1H), 4.27-4.20 (m, 2H), 4.10 (q, 1H), 4.03-3.93 (m, 3H), 3.28 (dd, 1H), 2.77 (dd, 1H), 1.29 (d, 3H).

A solution of lithium hydroxide monohydrate (1.16 g, 27.6 mmol) in 30% hydrogen peroxide (13.2 mL, 138 mmol) was prepared and was subsequently added slowly to a solution of phenylmethyl 3-hydroxy-3-{(1R)-1-methyl-2-oxo-2-[(4S)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]ethyl}azetidine-1-carboxylate (6.03 g, 13.8 mmol) in THF (80 mL) and water (20 mL) at 0° C. After the mixture was stirred for 1 h at rt, the hydrogen peroxide was quenched carefully with 1 M sodium sulfite (150 mL, 150 mmol). The THF was removed in vacuo, and the mixture was then acidified to pH=2 with concentrated hydrochloric acid. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient, 5% methanol: 95% dichloromethane to 10% methanol: 90% dichloromethane) to provide (2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)propanoic acid as a colorless oil (2.77 g, 9.9 mmol, 72% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.31 (m, 5H), 5.10 (s, 2H), 3.99 (s, 2H), 3.93 (s, 2H), 2.88 (q, 1H), 1.28 (d, 3H); MS (EI) for C₁₄H₁₇NO₅: 280 (MH⁺).

To a solution of (2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)propanoic acid (2.77 g, 9.9 mmol) in toluene (100 mL) was added triethylamine (1.52 mL, 10.9 mmol) followed by diphenyl phosphoryl azide (2.24 mL, 10.4 mmol). The mixture was heated to 80° C. for 2 h and was then cooled to rt. The volatile materials were removed in vacuo, and the residue was purified by column chromatography (gradient: 50% hexanes: 50% ethyl acetate up to 100% ethyl acetate). The desired product, (8R)-8-methyl-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylic acid phenylmethyl ester, was isolated as a viscous, colorless syrup (1.84 g, 6.6 mmol, 67% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.32 (m, 5H), 5.66 (br s, 1H), 5.12 (s, 2H), 4.34 (dd, 1H), 4.30 (dd, 1H), 4.17 (dd, 1H), 4.05 (dd, 1H), 3.98 (q, 1H), 1.34 (d, 3H).

To a solution of (8R)-8-methyl-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylic acid phenylmethyl ester (1.84 g, 6.6 mmol) in methanol (66 mL) was added wet 10% palladium on carbon (50% by mass, 500 mg). The resulting suspension was stirred under 1 atm of hydrogen for 1 h. The catalyst was then removed by filtration through celite. The filtrate was concentrated in vacuo to provide (8R)-8-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one as a white solid (0.99 g, quantitative yield). ¹H NMR (400 MHz, CDCl₃) δ 5.23 (br s, 1H), 4.07 (d, 1H), 4.02 (d, 1H), 3.92 (d, 1H), 3.79 (d, 1H), 3.58 (d, 1H), 1.38 (d, 3H); MS (EI) for C₆H₁₀N₂O₂: 143 (MH⁺).

A solution of (8R)-8-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one (937 mg, 6.6 mmol), acetic acid (0.756 mL, 13.2 mmol), and benzaldehyde (1.0 mL, 9.9 mmol) in methanol (65 mL) was treated with sodium cyanoborohydride (829 mg, 13.2 mmol) at rt for 30 min. The mixture was then cooled to 0° C., and 3 N hydrochloric acid (100 mL) was added. The methanol was then removed in vacuo. The resulting aqueous solution was washed with ethyl acetate. The ethyl acetate wash was back extracted with 1 N hydrochloric acid, and the aqueous acidic phases were combined and basified with potassium carbonate. The organic phase was discarded. The aqueous mixture was then extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The desired (8R)-8-methyl-2-(phenylmethyl)-5-oxa-2,7-diazaspiro[3.4]octan-6-one was obtained in 93% purity as a milky colorless liquid (1.33 g, 5.73 mmol, 87% yield). MS (EI) for C₁₃H₁₆N₂O₂: 233 (MH⁺).

To a solution of (8R)-8-methyl-2-(phenylmethyl)-5-oxa-2,7-diazaspiro[3.4]octan-6-one (1.33 g, 5.7 mmol) in dioxane (40 mL) and water (20 mL) was added barium hydroxide octahydrate (9.0 g, 28.5 mmol), and the mixture was heated to reflux for 2 h. After cooling to rt, the mixture was acidified with 3 N hydrochloric acid (10 mL) and dichloromethane (50 mL) was added. The biphasic mixture was treated with potassium carbonate (1.6 g, 11.4 mmol) and di-tert-butyl dicarbonate (2.11 g, 9.7 mmol). After stirring vigorously at rt for 17 h, solids were removed by filtration, and the layers were partitioned. The aqueous phase was extracted with dichloromethane, and the organic extracts were combined and dried over magnesium sulfate, filtered, and concentrated. The residue was taken up in methanol (60 mL) and was treated with potassium carbonate (3.0 g, 22 mmol) added in two portions over 4 h at reflux. After cooling, the methanol was removed in vacuo, and the residual solids were loaded directly on to a silica column. After purification (5% methanol:95% dichloromethane), 1,1-dimethylethyl {(1R)-1-[3-hydroxy-1-(phenylmethyl)azetidin-3-yl]ethyl}carbamate was obtained as a colorless syrup (1.07 g, 3.5 mmol, 62% yield). MS (EI) for C₁₇H₂₆N₂O₃: 307 (MH⁺).

To a solution of 1,1-dimethylethyl {(1R)-1-[3-hydroxy-1-(phenylmethyl)azetidin-3-yl]ethyl}carbamate (1.07 g, 3.5 mmol) in methanol was added wet 10% palladium on carbon (50% by mass, 250 mg). The resulting suspension was subjected to 1 atmosphere of hydrogen for 7 h, and an additional 250 mg of catalyst was added over the course of the reaction. The catalyst was then removed by filtration through celite. The filtrate was then concentrated in vacuo to provide 1,1-dimethylethyl [(1R)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate as a colorless syrup (800 mg, quantitative yield). MS (EI) for C₁₀H₂₀N₂O₃: 161 (M−tert-butyl+H).

To a solution of 1,1-dimethylethyl [(1R)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate (200 mg, 0.92 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (228 μL, 1.38 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (prepared according to the procedures described in Reference 1) (363 mg, 0.92 mmol). The mixture was stirred at rt for 16 h, after which the volatile materials were removed in vacuo. The residue was purified by column chromatography (50% hexanes:50% ethyl acetate) to provide 1,1-dimethylethyl {(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate as a colorless film (333 mg, 0.56 mmol, 61% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.47 (br s, 1H), 7.40 (dd, 1H), 7.32 (d, 1H), 7.12 (m, 1H), 6.81 (m, 1H), 6.61 (m, 1H), 4.74 (br d, 1H), 4.22 (d, 1H), 4.15-4.07 (m, 2H), 3.96 (br s, 1H), 3.77 (m, 1H), 1.43 (s, 9H), 1.18 (d, 3H); MS (EI) for C₂₃H₂₅F₃IN₃O₄: 536 (M−tert-butyl+H).

A solution of 1,1-dimethylethyl {(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate (333 mg, 0.56 mmol) in methanol (10 mL) was treated with hydrochloric acid (4 N in dioxane, 1.4 mL, 5.6 mmol) at 60° C. for 30 min. After cooling, the volatile materials were removed in vacuo to provide 3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol hydrochloride as a white solid (285 mg, 0.54 mmol, 97% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 7.83 (br s, 3H), 7.59 (dd, 1H), 7.39 (d, 1H), 7.34 (m, 1H), 7.21 (q, 1H), 6.69 (m, 1H), 6.65 (s, 1H), 4.25 (dd, 1H), 4.10 (dd, 1H), 3.98 (dd, 1H), 3.80 (m, 1H), 3.48 (m, 1H), 1.11 (dd, 3H); MS (EI) for C₁₈H₁₇F₃IN₃O₂: 492 (MH⁺)

To establish the enantiomeric excess (ee) of this material, 3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol hydrochloride (21 mg, 0.040 mmol) was dissolved in dichloromethane (400 μL) and was treated with diisopropylethylamine (20 μL, 0.12 mmol) and (R)-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride at rt for 15 min. An aliquot was removed and was analyzed by chiral HPLC. The diastereomeric excess of (2S)—N-{(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanamide was found to be 91%, and by extrapolation the ee of 3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol was also assigned to be 91%.

Example 28a

Using the sequence described above, beginning with (R)-4-benzyl-3-propionyl-2-oxazolidinone, 3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol was prepared using similar procedures except that the phenylmethyl 3-hydroxy-3-{(1S)-1-methyl-2-oxo-2-[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]ethyl}azetidine-1-carboxylate required additional recrystallizations from isopropanol. Using the same method described above in Example 28, 3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol was determined to have 98.4% ee. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 7.84 (br s, 3H), 7.59 (dd, 1H), 7.39 (d, 1H), 7.34 (m, 1H), 7.21 (q, 1H), 6.69 (m, 1H), 6.65 (s, 1H), 4.25 (dd, 1H), 4.10 (dd, 1H), 3.98 (dd, 1H), 3.80 (m, 1H), 3.48 (m, 1H), 1.11 (dd, 3H); MS (EI) for C₁₈H₁₇F₃IN₃O₂: 492 (MH⁺).

Example 28b

To 3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (87.4 mg, 0.18 mmol), prepared using procedures similar to those described in Example 28, was added formaldehyde (37% aqueous, 14 mg, 0.18 mmol) in methanol (2 mL) and sodium borohydride (7 mg, 0.18 mmol). The mixture was stirred for 3 h at rt, after which sodium borohydride (16 mg, 0.42 mmol) was added. Upon stirring an additional 1.25 h, more formaldehyde (37% aqueous, 1 drop) was added, and the mixture was stirred 3 days at rt. A further small spatula (˜50 mg) of sodium borohydride was then added, and the mixture was stirred at rt for 30 min. After quenching with 1 N HCl, the reaction mixture was purified directly by preparative HPLC. The clean material was converted to its hydrochloride salt to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol as a yellow solid (21.7 mg, 0.040 mmol, 22% yield). ¹H NMR (400 MHz, CD₃OD) δ 7.47 (dd, 1H), 7.36 (d, 1H), 7.31 (m, 1H), 7.06 (q, 1H), 6.62 (dt, 1H), 4.36 (dd, 1H), 4.21-3.91 (m, 3H), 3.44 (q, 1H), 2.66 (s, 3H), 1.29 (br m, 3H); MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 29 3-{[(1,1-Dimethylethyl)amino]methyl}-1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol

To a mixture of methyl 4-oxotetrahydrothiophene-3-carboxylate (1.75 g, 11 mmol) (commercially available or prepared using procedures similar to those described in Rossy et. al. J. Org. Chem. 1980, 45(4), 617-2) in 15 mL of ethanol was added 2-fluoro-4-iodoaniline (2.6 g, 11 mmol) followed by addition of several drops of acetic acid. The mixture was refluxed for 3 hrs. The mixture was cooled to room temperature and the product precipitated. This product was filtered off, washed with ethyl acetate, ether, dried in vacuo to afford the methyl 4-[(2-fluoro-4-iodophenyl)amino]-2,5-dihydrothiophene-3-carboxylate (1.7 g, 42%). ¹HNMR (d₆-DMSO): 9.80 (s, 1H), 7.71 (d, 1H), 7.49 (dd, 1H), 7.24 (t, 1H), 4.10 (t, 2H), 3.79 (t, 2H), 3.69 (s, 3H); MS (EI) for C₁₂H₁₁FINO₂S: 380 (MH⁺).

To a mixture of methyl 4-[(2-fluoro-4-iodophenyl)amino]-2,5-dihydrothiophene-3-carboxylate (1.2 g, 3.16 mmol) in 10 ml of anhydrous toluene was added 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (0.78 g, 3.16 mmol). The mixture was refluxed for 2 h. The mixture was cooled to 50° C. and concentrated in vacuo to dryness and cooled to room temperature. To the residue was added ethanol and the mixture was refluxed for several minutes, cooled to room temperature and light blue crystalline product was filtered off and dried in vacuo to afford methyl 4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylate (0.74 g, 62%). ¹HNMR (d₆-DMSO): 8.78 (s, 1H), 8.42 (d, 1H), 7.64 (d, 1H), 7.46 (d, 1H), 7.37 (t, 1H), 7.14 (s, 1H), 3.85 (s, 3H); MS (EI) for C₁₂H₉FINO₂S: 378 (MH⁺).

A mixture of methyl 4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylate (0.74 g, 1.96 mmol) in the solution of potassium hydroxide (0.3 g) in ethanol/water (4 ml/4 ml) was heated up to 60° C. and stirred at this temperature for 30 min. The mixture was cooled to room temperature, diluted with 4 ml of water and extracted with ether. The water layer was acidified with 1 N HCl to pH 2, the product precipitated and was filtered off, washed several times with water and dried in vacuo to afford 4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylic acid (0.59 g, 83%). ¹H NMR (d₆-DMSO): 13.20 (s, 1H), 9.13 (s, 1H), 8.35 (d, 1H), 7.62 (dd, 1H), 7.48-7.38 (m, 2H), 7.11 (s, 1H); MS (EI) for C₁₁H₇FINO₂S: 362 (MH⁻).

4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylic acid (200 mg, 0.551 mmol), 4-(dimethylamino)pyridine (202 mg, 1.65 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127 mg, 0.662 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 5 minutes and then 3-(hydroxymethyl)azetidin-3-ol hydrochloride (72 mg, 0.516 mmol) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 20% citric acid. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with 5% lithium chloride, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized from dichloromethane to afford 1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol (247 mg, 0.551 mmol, quantitative yield) as off-white crystals: MS (EI) for C₁₅H₁₄FIN₂O₃S: 449 (MH⁺).

1-({4-[(2-Fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol (247 mg, 0.551 mmol), was suspended in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (80 mg, 0.661 mmol), and 2,4,6-triisopropylbenzenesulfonyl chloride (183 mg, 0.604 mmol) at ambient for 15 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 30% ethyl acetate in hexanes) to give [1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl 2,4,6-tris(1-methylethyl)benzenesulfonate (101 mg, 0.141 mmol, 26% yield): MS (EI) for C₃₀H₃₆FIN₂O₅S₂: 715 (MH⁺).

[1-({4-[(2-Fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl 2,4,6-tris(1-methylethyl)benzenesulfonate (101 mg, 0.141 mmol) was dissolved in tetrahydrofuran (2 mL) and was treated with sodium hydride (60 wt % dispersion in oil; 17 mg, 0.425 mmol) at ambient for 20 minutes. Tetrahydrofuran (2 mL) and tert-butylamine (0.1 mL) were added and the mixture was stirred at ambient for 16 h. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC and the clean fractions were combined, neutralized with saturated sodium bicarbonate solution and the organic solvent was removed in vacuo. The remaining aqueous residue was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3-{[(1,1-dimethylethyl)amino]methyl}-1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol (8 mg, 0.016 mmol, 11% yield): ¹H NMR (400 MHz, d₆-DMSO): 9.64 (br, 1H), 8.08 (d, 1H), 7.59 (dd, 1H), 7.44 (dd, 1H), 7.36 (t, 1H), 7.12 (d, 1H), 4.39 (d, 1H), 4.22 (d, 1H), 4.03 (d, 1H), 3.80 (d, 1H), 2.68 (br, 2H) 1.04 (s, 9H); MS (EI) for C₁₉H₂₃FIN₃O₂S: 504 (MH⁺).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared:

Example 29(a)

3-[(dimethylamino)methyl]-1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol: ¹H NMR (400 MHz, CD₃OD): 7.91 (d, 1H), 7.46-7.41 (m, 2H), 7.33 (t, 1H), 7.00 (d, 1H), 4.66 (s, 1H), 4.49 (s, 1H), 4.30 (s, 1H), 4.15 (s, 1H), 3.54 (s, 1H), 3.17-3.13 (m, 3H), 2.90 (s, 2H), 1.87-1.83 (m, 3H); MS (EI) for C₁₇H₁₉FIN₃O₂S: 476 (MH⁺).

Example 29(b)

1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-amine: ¹H NMR (400 MHz, CD₃OD): 7.90 (d, 1H), 7.46-7.41 (m, 2H), 7.31 (t, 1H), 6.99 (d, 1H), 4.47 (br.s, 2H), 4.22-4.16 (m, 2H); MS (EI) for C₁₄H₁₃FIN₃OS: 418 (MH⁺).

Example 30 3-(1-aminoethyl)-1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)azetidin-3-ol

To a suspension of sodium hydride (72 mg, 1.75 mmol, 60% wt) in tetrahydrofuran (1 mL) cooled to 0° C. was added nitroethane (125 μL, 1.75 mmol). The suspension was allowed to warm to room temperature and was stirred for 15 minutes, then cooled back to 0° C. To the suspension was added dropwise a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (300 mg, 1.75 mmol, in 2 mL of tetrahydrofuran), prepared using procedures similar to those described in Reference 3. The suspension was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding 20% aqueous citric acid, and then was partitioned with ethyl acetate. The aqueous portion was extracted twice using ethyl acetate and the combined organic portion was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a colorless oil that was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes, the isolated product was concentrated in vacuo to afford 250 mg, 1.02 mmol (58%) of 1,1-dimethylethyl 3-hydroxy-3-(1-nitroethyl)azetidine-1-carboxylate as a colorless oil. ¹H NMR (400 MHz, DMSO): 6.46 (s, 1H), 5.01 (q, 1H), 4.24-3.97 (m, 2H), 3.77-3.60 (m, 2H), 1.41 (d, 3H), 1.39 (s, 9H).

1,1-Dimethylethyl 3-hydroxy-3-(1-nitroethyl)azetidine-1-carboxylate was dissolved in methanol (5 mL) and treated with 4 N HCl in dioxane. The solution was briefly heated to reflux and then was concentrated in vacuo to afford 178 mg, 0.98 mmol (96%) of 3-(1-nitroethyl)azetidin-3-ol hydrochloride as a white solid. ¹H NMR (400 MHz, DMSO): 9.30 (br s, 1H), 8.96 (br s, 1H), 5.12 (q, 1H), 4.44-4.38 (m, 1H), 4.22-4.17 (m, 1H), 3.94-3.87 (m, 1H), 3.85-3.77 (m, 1H), 1.44 (d, 3H).

A solution of 8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (150 mg, 0.35 mmol) (prepared using procedures similar to those described in US 2006030610 and US 2005054701), N,N-diisopropylethylamine (300 μL, 1.74 mmol), PyBOP (180 mg, 0.35 mmol) and 3-(1-nitroethyl)azetidin-3-ol hydrochloride (76 mg, 0.42 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was then partitioned between 5% aqueous lithium chloride, and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with 20% aqueous citric acid, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by column chromatography. Eluting with 5% methanol in dichloromethane, the isolated product was concentrated in vacuo to afford 195 mg, 0.35 mmol (100%) of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol as a yellow foam. ¹H NMR (400 MHz, CDCl₃): 8.28 (s, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 7.23 (br s, 1H), 6.55-6.51 (m, 1H), 6.02 (br s, 1H), 4.79 (q, 1H), 4.45-3.96 (4H), 1.56 (d, 3H). MS (EI) for C₂₀H₁₉ClFIN₆O₄: 560 (MH⁺).

To a solution of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol (195 mg 0.35 mmol) in tetrahydrofuran/water (5 mL, 4:1) was added iron powder (193 mg, 3.5 mmol) and ammonium formate (438 mg, 7.0 mmol). The mixture was stirred at 80° C. for 1 hour, then cooled to room temperature and filtered through a pad of celite. The celite was washed three times with boiling ethanol (20 mL). The filtrate was concentrated in vacuo and the residue was diluted with ethyl acetate. The precipitate which formed was filtered through a pad a celite and the filtrate was partitioned with water. The aqueous portion was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow residue which was purified by preparative reverse phase HPLC. The isolated product was concentrated in vacuo to afford 35 mg, 0.05 mmol (15%) of 3-(1-aminoethyl)-1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)azetidin-3-ol acetate salt as a white solid. ¹H NMR (400 MHz, DMSO): 8.79 (s, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.54 (d, 1H), 7.32 (d, 1H), 6.54-6.48 (m, 1H), 4.24-4.13 (m, 1H), 3.98-3.84 (m, 2H), 3.61-3.56 (m, 1H), 2.83 (q, 1H), 0.92-0.88 (m, 3H); MS (EI) for C₁₉H₁₈ClFIN₅O₂: 530 (MH⁺).

Example 31 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol

To a solution of 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (595 mg, 1.52 mmol), prepared using procedures similar to those described in Reference 5, in methanol (5 mL) was added catalytic palladium on carbon (5% wt). The heterogeneous mixture was stirred under a hydrogen gas atmosphere for 15 hours at ambient pressure and then was filtered. The filtrate was concentrated in vacuo to afford 385 mg, 1.50 mmol (98%) of 1,1-dimethylethyl 2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate as a colorless film without further purification.

A solution of 8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (78 mg, 0.18 mmol) (prepared using procedures similar to those described in US 2006030610 and US 2005054701), 1,1-dimethylethyl 2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate (46.7 mg, 0.18 mmol), 4-(dimethylamino)pyridine (66 mg, 0.55 mmol), and finally 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg, 0.21 mmol) in dimethylformamide (2 mL) was stirred at room temperature for 15 hours. The reaction mixture was partition between 5% aqueous lithium chloride and ethyl acetate and the aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with 1 N HCl, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by column chromatography. Eluting with ethyl acetate, the isolated product was concentrated in vacuo to afford 101 mg, 0.15 mmol (83%) of 1,1-dimethylethyl 2-[1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate as a white solid. The solid was immediately dissolved in methanol (5 mL) and 4 N HCl in dioxane was added. The solution was briefly heated to reflux and then was concentrated in vacuo. The resultant residue was purified by preparative reverse phase HPLC. Isolated product was concentrated in vacuo to afford 36 mg, 0.06 mmol (40%) of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol acetate as a white solid. ¹H NMR (400 MHz, DMSO): 8.78 (s, 1H), 8.19 (s, 0.5H), 8.15 (s, 0.5H), 8.00 (s, 1H), 7.62 (s, 1H), 7.55 (d, 1H), 7.31 (d, 1H), 6.54-6.49 (m, 1H), 4.24-4.12 (m, 1H), 3.97-3.86 (m, 2H), 3.63-3.56 (m, 1H), 2.98-2.90 (m, 1H), 2.50-2.40 (m, 1H), 1.72-1.61 (m, 1H), 1.56-1.43 (m, 2H), 1.32-1.14 (m, 2H), 1.07-0.94 (m, 1H); MS (EI) for C₂₂H₂₂ClFIN₅O₂: 570 (MH⁺).

Using the same or analogous synthetic techniques and/or substituting with alternative reagents, the following compounds of the invention were prepared:

Example 31(a)

1-({4-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 8.35 (s, 1H), 7.84-7.77 (m, 1H), 7.54-7.49 (m, 2H), 7.25 (d, 1H), 6.31-6.25 (m, 1H), 4.04-3.92 (m, 2H), 3.90 (s, 3H), 3.86-3.78 (m, 1H), 3.70-3.62 (m, 1H), 2.94-2.85 (m, 1H), 2.45-2.32 (m, 2H), 1.66-1.36 (m, 3H), 1.26-1.08 (m, 2H), 1.01-0.80 (m, 1H); MS (EI) for C₂₃H₂₄F₂IN₅O₂: 568 (MH⁺).

Example 31(a)

1-({7-[(4-bromo-2-chlorophenyl)amino]-8-chloroimidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol acetate salt: ¹H NMR (400 MHz, DMSO): 8.87 (s, 1H), 8.29 (s, 0.5H), 8.21 (s, 0.5H), 8.04 (s, 1H), 7.67-7.63 (m, 2H), 7.32 (d, 1H), 6.59 (d, 1H), 4.35-4.22 (m, 1H), 4.08-3.98 (m, 2H), 3.72-3.67 (m, 1H), 2.96-2.88 (m, 1H), 2.50-2.44 (m, 2H), 1.66-1.42 (m, 3H), 1.26-1.17 (m, 2H), 1.04-0.94 (m, 1H); MS (EI) for C₂₂H₂₂BrCl₂N₅O₂: 540 (MH⁺).

Example 32 3-(1-Amino-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol trifluoroacetate salt

Potassium tert-butoxide (1.393 g, 12.4 mmol) and [2-(1,3-dioxolan-2-yl)ethyl]-triphenylphosphonium bromide (5.51 g, 12.4 mmol) were stirred in ether (30 mL) at ambient for 1 h. Phenylmethyl 3-oxoazetidine-1-carboxylate (1.025 g, 5.0 mmol), prepared using procedures similar to those described in Reference 3, was added and the mixture was stirred at 35° C. for 6 h and then at ambient for 4 days. Mixture was filtered through celite and the solid was washed with ether. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ether in hexanes) gave phenylmethyl 3-[2-(1,3-dioxolan-2-yl)ethylidene]azetidine-1-carboxylate (220 mg, 0.761 mmol, 15% yield): ¹H NMR (400 MHz, CDCl₃): 7.39-7.28 (m, 5H), 5.43-5.35 (m, 1H), 5.11 (s, 2H), 4.89 (t, 1H), 4.56 (br d, 4H), 4.00-3.92 (m, 2H), 3.91-3.83 (m, 2H), 2.27 (br t, 2H).

Phenylmethyl 3-[2-(1,3-dioxolan-2-yl)ethylidene]azetidine-1-carboxylate (220 mg, 0.761 mmol), and 4-methylmorpholine N-oxide (287 mg, 2.45 mmol) were dissolved in acetone/water (4:1; 10 mL) and osmium tetroxide (4 wt. % in water; 0.05 mL) was added. The solution was stirred at ambient for 20 h, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave phenylmethyl 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]-3-hydroxyazetidine-1-carboxylate (244 mg, 0.755 mmol, 99% yield): ¹H NMR (400 MHz, CDCl₃): 7.38-7.28 (m, 5H), 5.11-5.07 (m, 3H), 4.14-4.01 (m, 4H), 3.96-3.86 (m, 5H), 3.47 (d, 1H), 2.97-2.94 (m, 1H), 1.98-1.84 (m, 2H).

Phenylmethyl 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]-3-hydroxyazetidine-1-carboxylate (235 mg, 0.728 mmol) was dissolved in methanol (5 mL) and treated with 5 wt % palladium on carbon (50 mg) under hydrogen at ambient for 1.5 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (0.729 mmol): MS (EI) for C₈H₁₅NO₄: 190 (MH⁺).

3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (287 mg, 0.730 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (178 mg, 1.46 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg, 0.88 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 10 minutes and then 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (0.729 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, gradient 90% ethyl acetate in hexanes to 100% ethyl acetate) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (148 mg, 0.262 mmol, 36% yield): MS (EI) for C₂₁H₂₀F₃IN₂O₅: 565 (MH⁺).

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (148 mg, 0.262 mmol), was dissolved in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (38 mg, 0.31 mmol), triethylamine (0.036 mL, 0.262 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (303 mg, 1.0 mmol) at 35° C. for 15 h. 2,4,6-Triisopropylbenzenesulfonyl chloride (100 mg, 0.33 mmol) was added and the mixture was stirred at 35° C. for 3.5 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 40-50% ethyl acetate in hexanes and then 100% ethyl acetate) to give 1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-(1,3-dioxolan-2-yl)ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (30 mg, 0.0361 mmol, 14% yield): MS (EI) for C₃₆H₄₂F₃IN₂O₇S: 831 (MH⁺).

1-[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-(1,3-dioxolan-2-yl)ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (50 mg, 0.060 mmol) was dissolved in tetrahydrofuran (1 mL) and was cooled to 0° C. Sodium hydride (60 wt % dispersion in oil; 7 mg, 0.18 mmol) was added and the mixture was stirred at 0° C. for 45 minutes. The mixture was quenched with saturated sodium bicarbonate solution and partitioned with ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 6-{[2-(1,3-dioxolan-2-ylmethyl)-1-oxa-5-azaspiro[2.3]hex-5-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline (31 mg, 0.057 mmol, 94% yield): MS (EI) for C₂₁H₁₈F₃IN₂O₄: 547 (MH⁺).

6-{[2-(1,3-Dioxolan-2-ylmethyl)-1-oxa-5-azaspiro[2.3]hex-5-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline (31 mg, 0.057 mmol) was dissolved in dimethylformamide (0.5 mL) and sodium azide (20 mg, 0.308 mmol) was added. The mixture was stirred at ambient for 22 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with water, brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 3-[1-azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (25 mg, 0.042 mmol, 74% yield): MS (EI) for C₂₁H₁₉F₃IN₅O₄: 590 (MH⁺).

3-[1-Azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (24 mg, 0.041 mmol) was dissolved in tetrahydrofuran (0.5 mL) and treated with 5% aqueous hydrochloric acid (0.5 mL) at ambient for 15 h. The mixture was neutralised with saturated sodium bicarbonate solution and was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3-azido-3-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]propanal (21 mg, 0.0385 mmol) which was suspended in ethanol (2 mL) and treated with sodium borohydride (5 mg, 0.132 mmol) at ambient for 2 h. The mixture was quenched with acetic acid (4 drops) and concentrated in vacuo. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 70-80% ethyl acetate in hexanes) gave 3-(1-azido-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (14 mg, 0.0255 mmol, 62% yield from 3-[1-azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol): ¹H NMR (400 MHz, CDCl₃): 8.33 (br s, 1H), 7.40 (dd, 1H), 7.32 (br d, 1H), 7.13 (br t, 1H), 6.83 (br q, 1H), 6.61 (ddd, 1H), 4.32-3.94 (m, 4H), 3.92-3.84 (m, 1H), 3.82-3.71 (m, 2H), 2.56 (br, 1H), 1.94 (br, 2H), 1.26 (br, 1H); MS (EI) for C₁₉H₁₇F₃IN₅O₃: 548 (MH⁺).

3-(1-Azido-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (14 mg, 0.0255 mmol) was dissolved in tetrahydrofuran and water (1:1, 0.5 mL) and polymer supported triphenylphosphine (˜3 mmol/g; 20 mg, 0.06 mmol) was added. The mixture was stirred at 55° C. for 1 h. Triphenylphosphine (10 mg, 0.038 mmol) was added and the mixture was stirred at 55° C. for 1.5 h. The mixture was filtered and the filtrate was purified by reverse phase HPLC to afford 3-(1-amino-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol trifluoroacetate salt (1.7 mg, 0.003 mmol, 10% yield): ¹H NMR (400 MHz, CD₃OD): 7.47 (dd, 1H), 7.36 (br d, 1H), 7.33-7.28 (m, 1H), 7.05 (br q, 1H), 6.62 (ddd, 1H), 4.38-4.26 (m, 1H), 4.18-4.00 (m, 2H), 3.98-3.88 (m, 1H), 3.78-3.67 (m, 2H), 3.61-3.56 (m, 1H), 1.87-1.70 (m, 2H); MS (EI) for C₁₉H₁₉F₃IN₃O₃: 522 (MH⁺).

Example 33 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(6-methylpiperidin-2-yl)azetidin-3-ol

To a solution of N,N-diisopropylamine (1.6 mL, 11.2 mmol) cooled to −78° C. in THF (15 mL) was added a 2.5 M solution of n-BuLi in hexane (4.5 mL, 11.2 mmol) dropwise over 5 minutes and the mixture was stirred at this temperature for an addition 15 minutes. 6-methyl-1-(phenylmethyl)piperidine-2-carbonitrile (2.4 g, 11.2 mmol) (prepared using procedures similar to those in Bonin et. al. Tet. Lett. 1982, 23(33), 3369-72) in THF (10 mL) was then added dropwise over 20 minutes and the reaction mixture was stirred for a further 30 minutes. Next a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (1.3 g, 7.5 mmol.), prepared using procedures similar to those in Example 3, in THF (10 mL) was added dropwise over 30 minutes. The reaction mixture was gradually warmed to room temperature and allowed to stir overnight. The reaction mixture was quenched with 10% citric acid and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate then filtered and concentrated in vacuo to give crude product as yellow oil. Further purification by flash chromatography (30% ethyl acetate in hexanes) afforded 1,1-dimethylethyl 3-[2-cyano-6-methyl-1-(phenylmethyl)piperidin-2-yl]-3-hydroxyazetidine-1-carboxylate as a pale yellow oil (0.2 g, 7% yield). ¹H NMR (400 MHz, CDCl₃): 7.17-7.40 (m, 5H), 4.42 (d, 1H), 4.04-4.18 (m, 1H), 3.83-4.00 (m, 1H), 3.70-3.75 (m, 2H), 1.70-1.87 (m, 4H), 1.45 (s, 3H), 1.41 (s, 9H), 1.22-1.26 (m, 1H), 1.13-1.18 (m, 2H); MS (EI) for C₂₂H₃₁N₃O₃: 386 (MH⁺).

To a stirred solution of 1,1-dimethylethyl 3-[2-cyano-6-methyl-1-(phenylmethyl)piperidin-2-yl]-3-hydroxyazetidine-1-carboxylate (180 mg, 0.47 mmol) in ethanol (1 mL) was added acetic acid (53.5 μL, 0.94 mmol) followed by sodium cyanoborohydride (58.7 mg, 0.94 mmol) and the reaction mixture stirred at 70° C. overnight. After cooling to room temperature the suspension was filtered through celite and the solid washed with additional ethanol. The filtrate was concentrated in vacuo and taken up in ethyl acetate (30 mL). The organic layer was washed with 2 M sodium hydroxide solution. The sodium hydroxide layer was separated and washed with ethyl acetate (10 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give crude 1,1-dimethylethyl 3-hydroxy-3-[6-methyl-1-(phenylmethyl)piperidin-2-yl]azetidine-1-carboxylate as yellow oil (60 mg, 36% yield). Crude product was used further without purification. ¹H NMR (400 MHz, CDCl₃): 7.22-7.35 (m, 5H), 4.08 (d, 1H), 3.85-3.96 (m, 3H), 3.57 (d, 1H), 3.33-3.36 (m, 1H), 2.91-3.06 (m, 2H), 1.63-1.70 (m, 4H), 1.44 (s, 9H), 1.23 (d, 3H), 1.05 (d, 2H); MS (EI) for C₂₁H₃₂N₂O₃: 361 (MH⁺).

To a solution of 1,1-dimethylethyl 3-hydroxy-3-[6-methyl-1-(phenylmethyl)piperidin-2-yl]azetidine-1-carboxylate (60 mg, 0.16 mmol) in methanol (0.5 mL) was added hydrogen chloride (4N in dioxane, 0.5 mL) and the reaction mixture stirred at 60° C. for one hour. The reaction mixture was cooled to room temperature and concentrated in vacuo and aezotroped 3 times from methanol and diethyl ether. On drying the hydrochloride salt of 3-[6-methyl-1-(phenylmethyl)piperidin-2-yl]azetidin-3-ol was obtained as a dark brown residue (40 mg, 81% yield), which was used further without purification. ¹H NMR (400 MHz, CD₃OD): 7.58-7.63 (m, 2H), 7.47-7.49 (m, 3H), 4.78 (d, 1H), 4.44-4.62 (m, 2H), 4.29 (s, 2H), 4.22-4.26 (m, 1H), 4.12-4.18 (m, 1H), 4.08 (s, 1H), 1.60-2.00 (m, 8H), 1.48 (d, 3H); MS (EI) for C₁₆H₂₅ClN₂O: 261 (MH⁺).

To a solution of 3-[6-methyl-1-(phenylmethyl)piperidin-2-yl]azetidin-3-ol hydrochloride (40 mg, 0.13 mmol) in ethyl acetate (3 mL) was added acetic acid (0.5 mL) and Pd/C (50 mg) and the mixture was hydrogenated at 35 psi for 3 hours. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The obtained residue was dissolved in a small amount of ethyl acetate and concentrated hydrochloric acid was added and the mixture was concentrated in vacuo to give the crude dihydrochloride salt of 3-[6-methylpiperidin-2-yl]azetidin-3-ol (20 mg, 54%). The crude product was used further without purification. ¹H NMR (400 MHz, CD₃OD): 4.20-4.40 (m, 1H), 4.00-4.10 (m, 1H), 3.60-3.90 (m, 2H), 1.50-2.00 (m, 6H), 1.45 (d, 3H), 1.26-1.30 (m, 1H); MS (EI) for C₁₉H₂₀Cl₂N₂O: 171 (MH⁺).

To a 0° C. solution of 3-[6-methylpiperidin-2-yl]azetidin-3-ol dihydrochloride (20 mg, 0.08 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (42 μL, 0.26 mmol) followed by 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (32 mg, 0.08 mmol), prepared using procedures similar to those described in Reference 1, and the reaction mixture stirred at 0° C. for 30 min. The mixture was diluted with acetonitrile and purified by preparative reverse phase HPLC (CH₃CN/H₂O with 0.1% TFA). Fractions were collected and lyophilized to give 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(6-methylpiperidin-2-yl)azetidin-3-ol acetate salt (7 mg, 16% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD): 7.44-7.50 (m, 1H), 7.34-7.37 (m, 1H), 7.28-7.32 (m, 1H), 7.02-7.12 (m, 1H), 6.60-6.63 (m, 1H), 4.10-4.30 (m, 2H), 3.95-4.09 (m, 2H), 3.80-3.95 (m, 1H), 3.55-3.65 (m, 1H), 3.34-3.36 (m, 1H), 1.90 (s, 3H), 1.62-1.84 (m, 6H), 1.40-1.52 (m, 1H), 1.33 (d, 3H); MS (EI) for C₂₂H₂₃F₃IN₃O₂: 546 (MH⁺).

Example 34 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-piperazin-2-ylazetidin-3-ol

To a solution of commercially available 1,4-bis(phenylmethyl)piperazine-2,5-dione (2.0 g, 6.8 mmol) in dry THF (50 mL) at −78° C. was added lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 3.4 mL, 6.8 mmol). The resulting reddish brown suspension was stirred for 23 min at −78° C., and then a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (770 mg, 4.5 mmol) in THF (10 mL) was added over 30 min by syringe pump. The mixture became a bright yellow solution as it was allowed to warm to room temperature over 3 hours. The mixture was quenched with saturated aqueous ammonium chloride. Water was added to dissolve precipitated salts, and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (60% ethyl acetate:40% hexanes) to provide 1,1-dimethylethyl 3-[3,6-dioxo-1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate as a colorless foam (1.04 g, 2.23 mmol, 50% yield). ¹H NMR (400 MHz, CDCl₃): 7.39-7.29 (m, 7H), 7.23-7.19 (m, 3H), 5.34 (d, 1H), 4.82 (d, 1H), 4.58 (d, 1H), 4.37 (d, 1H), 4.37 (d, 1H), 4.22 (d, 1H), 4.15 (s, 1H), 4.08 (d, 1H), 3.97 (d, 1H), 3.75 (d, 1H), 3.74 (d, 1H), 3.67 (d, 1H), 3.64 (br s, 1H), 1.43 (s, 9H).

A solution of 1,1-dimethylethyl 3-[3,6-dioxo-1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate (1.04 g, 2.2 mmol) in methanol (10 mL) was treated with hydrogen chloride in dioxane (4 N, 5.5 mL, 22 mmol) at 60° C. for 25 min. After cooling to room temperature the solution was concentrated. Ethyl acetate and 2 N hydrochloric acid were added to the residue and the phases were separated. The organic phase was discarded. The aqueous phase was basified with 5 M sodium hydroxide and the resulting solution was extracted 4 times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (85% dichloromethane:14% methanol:1% aqueous ammonium hydroxide) to provide 3-(3-hydroxyazetidin-3-yl)-1,4-bis(phenylmethyl)piperazine-2,5-dione as a colorless film (493 mg, 1.35 mmol, 61% yield). ¹H NMR (400 MHz, CDCl₃): 7.39-7.28 (m, 6H), 7.25-7.20 (m, 4H), 5.39 (d, 1H), 4.80 (d, 1H), 4.44 (d, 1H), 4.36 (d, 1H), 4.26 (d, 1H), 4.11 (s, 1H), 3.97 (d, 1H), 3.83 (d, 1H), 3.71 (d, 1H), 3.27 (m, 2H); MS (EI) for C₂₁H₂₃N₃O₃: 366 (MH⁺).

A solution 3-(3-hydroxyazetidin-3-yl)-1,4-bis(phenylmethyl)piperazine-2,5-dione (493 mg, 1.35 mmol) in ethyleneglycol dimethylether (12 mL) was treated with sodium borohydride (511 mg, 13.5 mmol) followed by slow addition of boron trifluoride-diethyl etherate. The reaction mixture was then heated to reflux for 3 hours. After cooling to 0° C., methanol (17 mL) was added followed by careful addition of concentrated hydrochloric acid (7 mL). The resulting mixture was heated to reflux for 70 minutes. After cooling to room temperature, insoluble residue was removed by filtration. The filtrate was concentrated to an aqueous mixture of about 10 mL in volume. This mixture was cooled to 0° C. and was then basified to pH 10 with 5 M sodium hydroxide (approximately 17 mL). Dichloromethane (10 mL) was then added followed by di-tert-butyl dicarbonate (442 mg, 2.03 mmol). The mixture was warmed to room temperature and stirred for 15 minutes. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (70% hexanes:30% ethyl acetate) to provide 1,1-dimethylethyl 3-[1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate as a white foam (408 mg, 0.93 mmol, 69% yield). ¹H NMR (400 MHz, CDCl₃): 7.35-7.24 (m, 10H), 4.12 (br s, 1H), 3.88 (d, 1H), 3.78-3.65 (m, 4H), 3.53 (d, 1H), 3.43 (d, 1H), 3.21 (m, 1H), 2.80 (br s, 1H), 2.66 (m, 1H), 2.57-2.37 (m, 4H), 1.41 (s, 9H); MS (EI) for C₂₆H₃₅N₃O₃: 438 (MH⁺).

To a solution of 1,1-dimethylethyl 3-[1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate (408 mg, 0.93 mmol) in methanol (15 mL) was added 10% palladium on carbon (wet), and the resulting suspension was subjected to an atmosphere of hydrogen for 21 hours. The catalyst was removed by filtration through celite, and the filter cake was rinsed with methanol. The combined filtrate was concentrated to provide 1,1-dimethylethyl 3-hydroxy-3-piperazin-2-ylazetidine-1-carboxylate as a brown syrup (227 mg, 0.88 mmol, 95% yield). ¹H NMR (400 MHz, CDCl₃): 3.94-3.76 (m, 5H), 3.12 (m, 1H), 3.01 (m, 1H), 2.94-2.81 (m, 3H), 2.78-2.70 (m, 2H); MS (EI) for C₁₂H₂₃N₃O₃: 258 (MH⁺).

To a solution of 1,1-dimethylethyl 3-hydroxy-3-piperazin-2-ylazetidine-1-carboxylate (227 mg, 0.88 mmol) and N,N-diisopropylethylamine (436 μL, 2.64 mmol) in THF (5 mL) was added 2-nitrobenzenesulfonyl chloride (195 mg, 0.88 mmol). The mixture was stirred at room temperature for 2 hours. The solution was concentrated and the residue was purified by column chromatography (95% dichloromethane:5% methanol) to provide 1,1-dimethylethyl 3-hydroxy-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidine-1-carboxylate as a white foam (308 mg, 0.70 mmol, 79% yield). ¹H NMR (400 MHz, CDCl₃): 7.98 (m, 1H), 7.72 (m, 2H), 7.64 (m, 1H), 3.96 (d, 1H), 3.94 (d, 1H), 3.85 (d, 1H), 3.79 (d, 1H), 3.79-3.73 (m, 2H), 3.11 (m, 1H), 3.05 (dd, 1H), 3.00 (br s, 1H), 2.94 (dt, 1H), 2.78 (dt, 1H), 2.68 (dd, 1H), 1.45 (s, 9H).

To a solution of 1,1-dimethylethyl 3-hydroxy-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidine-1-carboxylate (308 mg, 0.70 mmol) in methanol (10 mL) was added HCl in dioxane (4 N, 1.75 mL, 7.0 mmol), and the mixture was heated to 60° C. for 30 minutes. The solution was concentrated to provide 3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol as a sticky white solid. This material was dissolved in dichloromethane (7 mL). To the solution was added N,N-diisopropylethylamine (1.16 mL, 7.0 mmol) followed by 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (277 mg, 0.7 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 16 hours. The solution was concentrated and the residue was purified by column chromatography (95% dichloromethane:5% methanol) to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol as a pale yellow foam (453 mg, 0.63 mmol, 90% yield). ¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.96 (dd, 1H), 7.71 (m, 2H), 7.53 (dd, 1H), 7.39 (dd, 1H), 7.33 (d, 1H), 7.15 (m, 1H), 6.84 (br s, 1H), 6.62 (m, 1H), 4.29-3.97 (br m, 4H), 3.79-3.62 (m, 3H), 3.26-2.99 (br m, 3H), 2.92-2.62 (br m, 3H); MS (EI) for C₂₆H₂₃F₃IN₅O₆S: 718 (MH⁺).

To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol (139.4 mg, 0.19 mmol) in DMF (1 mL) was added potassium carbonate (79 mg, 0.57 mmol) and thiophenol (21 μL, 0.21 mmol). The mixture was stirred for 45 min at room temperature then quenched with water. The aqueous mixture was extracted twice with ethyl acetate, and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by preparative reverse phase HPLC to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-piperazin-2-ylazetidin-3-ol as a white solid (26.8 mg, 0.05 mmol). ¹H NMR (400 MHz, CD₃OD): 7.45 (dd, 1H), 7.36 (m, 1H), 7.32 (m, 1H), 7.03 (m, 1H), 6.62 (ddd, 1H), 4.51 (br dd, 1H), 4.31 (br dd, 1H), 4.17-3.92 (m, 4H), 3.73-3.56 (m, 3H), 3.46 (br m, 1H), 3.26 (m, 1H); MS (EI) for C₂₀H₂₀F₃IN₄O₂: 533 (MH⁺).

Example 36 1,1-Dimethylethyl {(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate

To a suspension of 4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 0.13 mmol) in DMF (2 mL), prepared using similar procedures to those described in Reference 4, at room temperature was added 1-hydroxybenzotriazole (36.3 mg, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.27 mmol) and the reaction was stirred for 2 hours. 1,1-Dimethylethyl [(1S)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate (30 mg, 0.13 mmol), prepared using procedures similar to those in Example 28, and triethylamine (0.04 mL) were added and the mixture was stirred for 15 hours. The reaction mixture was partitioned between saturated sodium chloride and ethyl acetate. The organic layer was washed with 5% lithium chloride solution, saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product as yellow oil. The oil was purified by column chromatography (silica gel, ethyl acetate) to afford 1,1-dimethylethyl {(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate as a yellow oil (55 mg, 73% yield): ¹H NMR (400 MHz, CDCl₃): 10.24-10.23 (m, 1H), 7.52-7.50 (m, 2H), 7.12-7.07 (m, 1H), 6.10-6.09 (m, 1H), 5.13-5.09 (m, 1H), 4.91-4.82 (m, 1H), 4.60-4.39 (m, 2H), 4.10-4.08 (m, 1H), 4.00-3.87 (m, 2H), 3.70 (d, 3H), 1.43 (s, 9H), 1.24-1.20 (m, 3H); MS (EI) for C₂₂H₂₇FIN₅O₅: 588 (MH⁺).

Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared:

Example 36(a)

1,1-Dimethylethyl {(1S)-1-[1-({5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate: ¹H NMR (400 MHz, CDCl₃): 7.95 (s, 1H), 7.45-7.44 (m, 1H), 7.33-7.27 (m, 2H), 7.15-7.12 (m, 1H), 6.50-6.47 (m, 1H), 4.82-4.74 (m, 1H), 4.17-3.92 (m, 4H), 3.86 (s, 3H), 3.74-3.60 (m, 1H), 1.40 (s, 9H), 1.11-1.06 (m, 3H). MS (EI) for C₂₅H₂₈BrClFN₅O₄: 598 (MH⁺) with a chloro, bromo isotope pattern.

Example 36(b)

1,1-Dimethylethyl (2S)-2-[1-({5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate: MS (EI) for C₂₈H₃₂BrClFN₅O₄: 638 (MH⁺) with a chloro, bromo isotope pattern.

Example 37 6-({3-[(1S)-1-aminoethyl]-3-hydroxyazetidin-1-yl}carbonyl)-5-[(2-fluoro-4-iodophenyl)amino]-2-methylpyridazin-3(2H)-one acetate salt

1,1-Dimethylethyl {(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate (55 mg, 0.09 mmol), prepared using procedures similar to those described in Example 36, was taken up in methanol (2 mL) and hydrochloric acid (4N in dioxane, 1 mL, 4 mmol) was added and the reaction was stirred at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 6-({3-[(1S)-1-aminoethyl]-3-hydroxyazetidin-1-yl}carbonyl)-5-[(2-fluoro-4-iodophenyl)amino]-2-methylpyridazin-3(2H)-one acetate as yellow solid (40 mg, 87%). ¹H NMR (400 MHz, CDCl₃): 10.17 (d, 1H), 7.52-7.46 (m, 2H), 7.09 (t, 1H), 6.13-6.12 (m, 1H), 4.51-4.48 (m, 2H), 4.18-4.03 (m, 2H), 3.73 (d, 3H), 3.35-3.28 (m, 1H), 3.22-2.80 (br, 3H), 1.21-1.19 (m, 3H); MS (EI) for C₁₇H₁₉FIN₅O₃: 488 (MH⁺).

Using the same or analogous synthetic techniques and/or substituting with alternative reagents, the following compounds of the invention were prepared:

Example 37(a)

3-[(1S)-1-Aminoethyl]-1-({5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6-yl}carbonyl)azetidin-3-ol hydrochloride. MS (EI) for C₂₀H₂₀BrClFN₅O₂: 498 (MH⁺) with a chloro, bromo isotope pattern

Example 37(b)

1-({5-[(4-Bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol hydrochloride. ¹H NMR (400 MHz, CD₃OD): 9.42 (s, 1H), 7.97-7.96 (m, 1H), 7.57 (s, 1H), 7.30-7.27 (m, 1H), 6.70-6.66 (m, 1H), 4.60-4.55 (m, 1H), 4.28 (t, 1H), 4.19 (s, 3H), 4.13-3.98 (m, 2H), 3.38-3.32 (m, 2H), 3.00 (t, 1H), 1.86-1.30 (m, 6H). MS (EI) for C₂₃H₂₄BrClFN₅O₂. HCl: 538 (MH⁺) with a chloro, bromo isotope pattern

Example 38 1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol

3-[(2-Fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid (200 mg, 0.559 mmol), prepared using procedures similar to those described in WO 2006/045514, was suspended in DMF (7 mL) and 1-hydroxybenzotriazole (151 mg, 1.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (214 mg, 1.12 mmol) were added. The mixture was stirred at ambient for 10 minutes and then triethylamine (0.078 mL, 0.559 mmol) was added. After a further 20 minutes, 1,1-dimethylethyl (2S)-2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate (143 mg, 0.559 mmol), prepared using similar procedures to those described in Example 22(a) and 22(b), and triethylamine (0.16 mL, 1.15 mmol) were added and the mixture was stirred for 15 hours. The mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic portion was washed with 5% lithium chloride and twice with saturated sodium bicarbonate, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 60-80% ethyl acetate in hexanes) to give 1,1-dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (368 mg, 0.587 mmol, 74% yield): ¹H NMR (400 MHz, CDCl₃): 8.73 (br m, 1H), 8.62 (br s, 1H), 8.14 (d, 1H), 7.47 (dd, 1H), 7.43-7.39 (m, 1H), 7.20-7.12 (m, 2H), 4.38-4.21 (m, 2H), 4.16-4.01 (m, 2H), 4.01-3.88 (m, 1H), 3.44-3.30 (m, 1H), 2.98-2.83 (m, 1H), 2.00-1.88 (m, 1H), 1.71-1.50 (m, 6H), 1.44 (s, 9H); MS (EI) for C₂₅H₃₀FIN₄O₄: 597 (MH⁺).

1,1-Dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (24 mg, 0.040 mmol) was dissolved in methanol (2 mL) and treated with 4 N hydrochloric acid in dioxane (0.25 mL, 1 mmol) at reflux for 20 minutes. The mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol acetate (14 mg, 0.025 mmol, 63% yield): ¹H NMR (400 MHz, d₆-DMSO): 8.62 (br s, 1H), 8.46 (s, 1H), 8.18 (dd, 1H), 7.65 (dd, 1H), 7.45 (d, 1H), 7.37 (t, 1H), 7.16-7.08 (m, 1H), 4.25 (dd, 1H), 4.04 (dd, 1H), 3.90 (t, 1H), 3.70 (d, 1H), 2.95 (br d, 1H), 2.52-2.42 (m, 2H), 1.78-1.68 (m, 1H), 1.57 (br t, 1H), 1.47 (br d, 1H), 1.35-1.13 (m, 2H), 1.10-0.96 (m, 1H); MS (EI) for C₂₀H₂₂FIN₄O₂: 497 (MH⁺).

Example 39 1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol

1,1-Dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (80 mg, 0.134 mmol), prepared using procedures similar to those described in Example 38, was dissolved in dichloromethane (3 mL) and treated with 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135 mmol) at ambient for 7 hours. 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135 mmol) was added and the mixture was stirred for 15 hours. The mixture was purified by column chromatography (silica gel, 0-10% ethanol in ethyl acetate) to give 1,1-dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (57 mg, 0.093 mmol, 69% yield): ¹H NMR (400 MHz, CDCl₃): 9.38 (s, 1H), 8.00 (s, 1H), 7.68 (dd, 1H), 7.51 (dd, 1H), 7.46 (d, 1H), 7.19 (br d, 1H), 7.09 (t, 1H), 5.78 (br, 1H), 4.44-3.98 (m, 3H), 3.98-3.87 (m, 1H), 3.49-3.39 (m, 1H), 3.07-2.88 (m, 1H), 2.01-1.91 (m, 1H), 1.70-1.47 (m, 6H), 1.45 (s, 9H); MS (EI) for C₂₅H₃₀FIN₄O₅: 613 (MH⁺).

1,1-Dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (57 mg, 0.093 mmol) was dissolved in methanol (2 mL) and treated with 4N hydrochloric acid in dioxane (0.25 mL, 1 mmol) at 50° C. for 2.25 hours. The mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol acetate (35 mg, 0.061 mmol, 66% yield): ¹H NMR (400 MHz, d₆-DMSO): 7.83 (s, 1H), 7.72 (dt, 2H), 7.55-7.51 (m, 1H), 7.47-7.41 (m, 1H), 7.24 (t, 1H), 4.45-4.32 (m, 1H), 4.14-3.95 (m, 2H), 3.72 (d, 1H), 2.97 (d, 1H), 2.58-2.43 (m, 2H), 1.80-1.73 (m, 1H), 1.67-1.55 (m, 1H), 1.49 (br d, 1H), 1.38-1.16 (m, 2H), 1.16-1.01 (m, 1H); MS (EI) for C₂₀H₂₂FIN₄O₃: 513 (MH⁺).

Example 40 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol

To 3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (87.4 mg, 0.18 mmol), prepared using similar procedures to those described in Example 28, was added formaldehyde (37% aqueous, 14 mg, 0.18 mmol) in methanol (2 mL) and sodium borohydride (7 mg, 0.18 mmol). The mixture was stirred for 3 h at rt, after which sodium borohydride (16 mg, 0.42 mmol) was added. Upon stirring an additional 1.25 h, more formaldehyde (37% aqueous, 1 drop) was added, and the mixture was stirred 3 days at rt. A further small spatula (˜50 mg) of sodium borohydride was then added, and the mixture was stirred at rt for 30 min. After quenching with 1 N HCl, the reaction mixture was purified directly by preparative HPLC. The clean material was converted to its hydrochloride salt to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol as a yellow solid (21.7 mg, 0.040 mmol, 22% yield). ¹H NMR (400 MHz, CD₃OD) δ 7.47 (dd, 1H), 7.36 (d, 1H), 7.31 (m, 1H), 7.06 (q, 1H), 6.62 (dt, 1H), 4.36 (dd, 1H), 4.21-3.91 (m, 3H), 3.44 (q, 1H), 2.66 (s, 3H), 1.29 (br m, 3H); MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Biological Example 1 Biochemical Assay

For a biochemical measurement of MEK1 inhibitory activity, compounds of the invention were screened in a triple coupled cRaf-MEK-ERK2 assay using ALPHASCREEN (Registered Trademark of Perkin Elmer) technology (Perkin Elmer). The compound of the invention, 0.5 μL of 100% DMSO stock solution, is diluted into an assay buffer composed of 20 mM Tris (pH=7.5), 10 mM magnesium chloride, 0.03% CHAPS and 1 mM DTT. Subsequently, 10 μL of substrate mixture is added composed of unactive MEK1 (3 nM), ATP (50 μM), unactive ERK2 (4 nM), biotinylated MBP peptide (b-FFKNIVTPRTPPPSQGK, 1 μM) and antiphospho MBP peptide (0.5 nM). The mixture is then gently shaken for 30 minutes at room temperature followed by addition of active cRaf (5 μL at 0.5 nM) to initiate reaction. The mixture is then shaken for 100 minutes at room temperature then quenched by addition of 10 μL of a mixture of 5 μg/mL streptavidin donor beads and 5 μg/mL protein A acceptor beads in detection buffer (75 mM Hepes pH=7.5, 300 mM sodium chloride, 120 mM EDTA, 0.3% BSA and 0.03% Tween), followed by incubation overnight and signal detection on an ALPHAQuest® (Registered Trademark of Perkin Elmer) plate reader (Perkin Elmer).

Compounds of the invention are inhibitors of MEK. The extent to which these compounds are MEK inhibitors can be determined by one of ordinary skill in the art. In particular, the compounds can be tested in the assay described in Biological Example 1. When tested in that assay, compounds of the invention demonstrated the ability to bind to MEK. In one embodiment of the invention, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 4 μM or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 3 μM or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 2 μM or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 1.6 μM or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 1 μM or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 0.7 μM or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 0.3 μM or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 0.2 μM or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 0.1 μM or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 0.05 μM or less.

Biological Example 2 Endogenous ERK Phosphorylation ELISA Assay

MDA-MB-231T (ATCC), Calu-6 (ATCC), HCT 116 (ATCC), A2058 (ATCC), and A375 (ATCC) cells were seeded at 20000, 30000, 30000, 20000, and 30000 cells/well, respectively, onto black 96-well microtiter plates (Costar 3904), in DMEM (Cellgro) containing 10% FBS (Heat-Inactivated, Cellgro), 1% NEAA (Cellgro), and 1% Pen/Strep (Cellgro). SK-MEL-28 (ATCC) cells were seeded at 20000 cells/well in MEM (ATCC) containing 10% FBS (Heat-Inactivated, Cellgro), and 1% Pen/Strep (Cellgro). The cells were then incubated at 37° C., 5% CO₂ for 24 h. Serum starvation was performed by replacing the medium with serum-free DMEM or MEM for an additional 24 h. Serial dilutions of test compounds in fresh serum-free medium in a final concentration of 0.3% DMSO (vehicle) were added to the cells and incubated for 1 h. Negative control wells were in serum-free medium+0.3% DMSO only. After treatment, the medium was removed and cells were fixed with 4% formaldehyde, followed by quenching of endogenous peroxidases with 0.6% H₂O₂. Plates were then blocked (10% FBS, Cellgro) and incubated with mouse monoclonal anti-phospho-p44/42 MAPK, E10 (1:2000, Cell Signaling), followed by secondary antibody (HRP-conjugated, goat anti-mouse IgG, 1:3000 from Jackson ImmunoResearch Laboratories, Inc). Washing of the plates was performed with PBS-T (0.1% Triton X-100) in between all incubation steps. A luminol-based substrate solution was then added and plates read using the Victor Wallac machine. IC₅₀ values were determined based on total ERK phosphorylation with compound treatment versus total ERK phosphorylation with 0.3% DMSO treatment alone.

Biological Example 3 BrdU Cell Proliferation Assay

MDA-MB-231T (ATCC), Calu-6 (ATCC), HCT 116 (ATCC), A2058 (ATCC), A375 (ATCC), and Colo-205 (ATCC) cells were plated at densities of 2500, 3500, 3500, 2500, 3500, and 15000 cells/well onto 96-well microtiter plates (Cat# 3904, Costar), in DMEM (Cellgro) containing 10% FBS (Heat Inactivated, Cellgro), 1% Pen/Strep (Cellgro), and 1% NEAA (Cellgro). SK MEL-28 (ATCC) and WM-266-4 (ATCC) were plated at densities of 2000 and 6000 cells/well in MEM (ATCC) containing 10% FBS (Heat-Inactivated, Cellgro), and 1% Pen/Strep (Cellgro). The cells were incubated overnight at 37° C., 5% CO₂ for 18 h. The next day, cells were treated with a serial dilution of compound in medium (containing a final concentration of 0.3% DMSO). Triplicate wells were used for each compound concentration. The control wells received 0.3% DMSO media. The cultures were incubated at 37° C., 5% CO₂ for an additional 48 h. The cells were assayed for proliferation according to the “Cell Proliferation ELISA, Bromo Deoxyuridine (BrdU) (chemiluminescence) kit” from Roche. The cells were treated with the BrdU labeling solution and then fixed with FixDenat solution. Anti-BrdU-POD (PerOxiDase) conjugate was added to the cells, after which the plates were washed 3× with 1×PBS. Substrate solution was added, and the plates were read for luminescence using the Victor Wallac machine. IC₅₀ values were calculated based on the cell proliferation with compound treatment compared to the vehicle control.

Biological Example 4 In Vivo Mouse Models

The ability of a MEK inhibitor, administered as monotherapy (i.e. not in combination with another cancer treatment), to inhibit the growth of the following tumors in mice was examined. The models can also be used by one of ordinary skill in the art to determine the desirability of a particular combination of a MEK inhibitor with another cancer treatment.

Female athymic nude mice (NCr) 5-8 weeks of age and weighing approximately 20 g were purchased from Taconic (Germantown, N.Y.). Prior to initiation of a study, the animals were allowed to acclimate for a minimum of 48 h. During these studies, animals were provided food and water ad libitum and housed in a room conditioned at 70-75° F. and 60% relative humidity. A 12 h light and 12 h dark cycle was maintained with automatic timers.

Colo-205 human colorectal carcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37° C. in a humidified, 5% CO₂ atmosphere. On day 0, cells were harvested by trypsinization, and 3×10⁶ cells (passage #3, 92% viability) in 0.1 ml ice-cold Hank's balanced salt solution were implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice.

A375 human melanoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37° C. in a humidified, 5% CO₂ atmosphere. On day 0, cells were harvested by trypsinization, and 5×10⁶ cells (passage #8, >99% viability) in 0.1 mL ice-cold Hank's balanced salt solution were implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice.

A2058 human melanoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37° C. in a humidified, 5% CO₂ atmosphere. On day 0, cells were harvested by trypsinization, and 3×10⁶ cells (passage #5, 80% viability) in 0.1 mL ice-cold Hank's balanced salt solution were implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice.

MDA-MB-231 human breast adenocarcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37° C. in a humidified, 5% CO₂ atmosphere. On day 0, cells were harvested by trypsinization, and 1×10⁶ cells (passage #6, >99% viability) in 0.1 mL ice-cold Hank's balanced salt solution were implanted subcutaneously into the mammary fat pad of 5-8 week old female athymic nude mice.

Calu-6 human lung anaplastic carcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37° C. in a humidified, 5% CO₂ atmosphere. On day 0, cells were harvested by trypsinization, and 5×10⁶ cells (passage #8, 96% viability) in 0.1 mL ice-cold Hank's balanced salt solution were implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice.

For subcutaneous or intradermal tumors, the mean tumor weight of each animal in the respective control and treatment groups was determined twice weekly during the study. Tumor weight (TW) was determined by measuring perpendicular diameters with a caliper, using the following formula: tumor weight (mg)=[tumor volume=length (mm)×width² (mm²)]/2.

Percent inhibition of tumor growth (TGI) is determined with the following formula:

$\left( {1 - \left( \frac{\left( {X_{f} - X_{0}} \right)}{\left( {Y_{f} - X_{0}} \right)} \right)} \right)*100$ where X₀=average TW of all tumors on group day; X_(f)=TW of treated group on Day f; Y_(f)=TW of vehicle control group on Day f

If tumors regress below their starting sizes, then the percent tumor regression is determined with the following formula:

$\left( \frac{\left( {X_{0} - {Xf}} \right)}{X_{0}} \right)*100$ TGI is calculated individually for each tumor to obtain a mean±SEM value for each experimental group. Statistical significance is determined using the 2-tailed Student's t-test (significance defined as P<0.05).

Biological Example 5 WM-266-4 Human Melanoma Xenograft Model

The WM-266-4 human melanoma cell line is PTEN-deficient, and harbors a heterozygous activating mutation in the gene encoding B-Raf. Therefore, the ability of a MEK inhibitor administered as monotherapy, and in combination with the mTOR inhibitor rapamycin, was examined to inhibit the growth of WM-266-4 xenograft tumors in nude mice.

Tumors were established in female nude mice and staged when the tumors reached 112±6 mg. The MEK compound was dosed orally (in the morning) at 10 mg/kg qd and rapamycin dosed intraperitoneally (in the afternoon, ˜7 h after the morning dose) at 5 mg/kg qd were administered as single agents or in combination. The MEK compound administered as monotherapy caused significant tumor growth inhibition Coadministration of rapamycin and the MEK compound resulted in efficacy significantly superior (p<0.001) to that achieved with either agent given alone (95% TGI, compared with TGI of 60% and 82%).

Summary of Growth Inhibition of WM-266-4 Tumors by a MEK Inhibitor Administered Alone or in Combination with Rapamycin

AM Test Dose PM Test TGI^(a) P value Article (qd × 14) Article Dose Schedule (%) (vs. Veh) Vehicle 10 mL/kg PO Vehicle 10 mL/kg IP^(b) qd × 14 — — MEK 10 mg/kg PO Vehicle 10 mL/kg IP qd × 14 82 2.67E−09 compound Vehicle 10 mL/kg PO Rapamycin 5 mg/kg IP qd × 14 60 1.39E−06 MEK 10 mg/kg PO Rapamycin 5 mg/kg IP qd × 14 95 1.29E−10 compound ^(a)TGI, tumor growth inhibition; ^(b)IP, administered intraperitoneally.

Pharmaceutical Composition Examples

The following are representative pharmaceutical formulations containing a compound of Formula I.

Tablet Formulation

The following ingredients are mixed intimately and pressed into single scored tablets.

Ingredient Quantity per tablet, mg compound of this invention 400 Cornstarch 50 croscarmellose sodium 25 Lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

Ingredient Quantity per tablet, mg compound of this invention 200 lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oral administration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg distilled water q.s. to 100 mL

Injectable Formulation

The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention 1.2 g sodium acetate buffer solution 0.4 M 2.0 mL HCl (1 N) or NaOH (1 M) q.s. to suitable pH water (distilled, sterile) q.s.to 20 mL

All of the above ingredients, except water, are combined and heated to 60-70.degree. C. with stirring. A sufficient quantity of water at 60.degree. C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. to 100 g.

Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol®H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:

Ingredient Quantity per tablet, mg compound of this invention 500 Witepsol ® H-15 balance

The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted. 

1. A method of treating melanoma in a patient, which method comprises administering to said patient a therapeutically effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, or administering a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier, excipient, or diluent in combination with one or more chemotherapeutic agent(s), where the one or more chemotherapeutic agent(s) is rapamycin or a rapamycin analogue; wherein the compound is that where R³ and R⁴ are independently hydrogen, halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN), —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴ together with the carbon to which they are attached form C(O) or C(═NOH); m is 0, 1, or 2; R⁸, R^(8′) and R^(8″) are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, optionally substituted cycloalkyl, optionally substituted cycloalkyloxycarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkyloxycarbonyl, nitro, cyano, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ is optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), —NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or alkyl and R^(34a) is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl), —SO₂NR³⁵R^(35a) (where R³⁵ is hydrogen or alkyl and R^(35a) is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl), —NR³²C(O)R^(32a) (where R³² is hydrogen or alkyl and R^(32a) is alkyl, alkenyl, alkoxy, or cycloalkyl), —NR³OR^(30′) (where R³⁰ and R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl), and —C(O)NR³³R^(33a) (where R³³ is hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or cycloalkyl); R⁹ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, or five groups selected from halo, hydroxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, and dialkylamino; R²⁵ and R^(25b) are independently hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, or optionally substituted aryl; and R^(25a) is hydrogen, alkyl, or alkenyl.
 2. The method of claim 1 where the one or more chemotherapeutic agent(s) is rapamycin.
 3. The method of claim 1 where the compound is selected from the group consisting of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}- carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-one; 6-(azetidin-1-ylcarbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- (hydroxymethyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- (trifluoromethyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- prop-2-en-1-ylazetidin-3-ol; 3-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]propane-1,2-diol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ethylazetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- methylazetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ethenylazetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-one; oxime; [1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol; 1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]ethane-1,2-diol; 1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- hydroxyazetidine-3-carboxamide; 1,1-dimethylethyl [1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- (pyrrolidin-1-ylmethyl)azetidin-3-ol; 3-[(diethylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(dimethylamino)methyl]azetidin-3-ol; N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- prop-2-en-1-ylazetidine-3-carboxamide; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-methylpropanamide; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]formamide; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-3,4- dihydroxybutanamide; methyl [1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate; N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(2R)-piperidin-2-yl]azetidin-3-ol; (R)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- pyrrolidin-2-ylazetidin-3-ol; (S)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- pyrrolidin-2-ylazetidin-3-ol; 3-(aminomethyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; (R)-(3-(1-aminopropyl)-3-hydroxyazetidin-1-yl)(3,4-difluoro-2-(2-fluoro- 4-iodophenylamino)phenyl)methanone; (S)-(3-(1-aminopropyl)-3-hydroxyazetidin-1-yl)(3,4-difluoro-2-(2-fluoro- 4-iodophenylamino)phenyl)methanone; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- ethylazetidine-3-carboxamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2- hydroxyethyl)azetidine-3-carboxamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2- piperidin-1-ylethyl)azetidine-3-carboxamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- phenylazetidine-3-carboxamide; N-[2-(diethylamino)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- (morpholin-4-ylmethyl)azetidin-3-ol; 1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}piperidin-4-ol; 3-{[bis(2-hydroxyethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-(4-methylpiperazin-1- yl)acetamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(4- methylpiperazin-1-yl)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(4- methyl-1,4-diazepan-1-yl)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[methyl(1-methylpyrrolidin-3-yl)amino]methyl}azetidin-3-ol; 3-(1,4′-bipiperidin-1′-ylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N,N-bis(2- hydroxyethyl)glycinamide; 3-({4-[2-(diethylamino)ethyl]piperazin-1-yl}methyl)-1-({3,4-difluoro-2- [(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-hydroxyethyl)(methyl)amino]methyl}azetidin-3-ol; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-piperidin-1- ylacetamide; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N3-(2-hydroxyethyl)- N3-methyl-beta-alaninamide; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N3,N3-bis(2- hydroxyethyl)-beta-alaninamide; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2,N2- diethylglycinamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- methylazetidin-3-amine; 1-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N,N- dimethylpyrrolidin-3-amine; 2-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]amino}ethanol; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]propane-1,3-diamine; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- methyl-N-(2-pyridin-2-ylethyl)azetidin-3-amine; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2-methylglycinamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- ethylazetidin-3-amine; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2- methylpropyl)azetidin-3-amine; N-(cyclopropylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine; N-(cyclohexylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine; N-(cyclopentylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine; 3-(azetidin-1-ylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- [(2,3-dihydroxypropyl)oxy]azetidine-3-carboxamide; N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]glycinamide; 6-({3-[(dimethylamino)methyl]azetidin-1-yl}carbonyl)-2,3-difluoro-N-(2- fluoro-4-iodophenyl)aniline; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1-methylethyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- (3,4-dihydroxybutyl)azetidine-3-carboxamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- (2,3-dihydroxypropyl)azetidine-3-carboxamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidine-3-carboxamide; 6-{[3-(aminomethyl)-3-(methyloxy)azetidin-1-yl]carbonyl}-2,3-difluoro- N-(2-fluoro-4-iodophenyl)aniline; N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}acetamide; 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-{[(1- methylethyl)amino]methyl}azetidin-1-yl)carbonyl]aniline; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(ethylamino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{2- [(1-methylethyl)amino]ethyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2- hydroxy-1,1-dimethylethyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- 2{1,1-dimethyl--[(1-methylethyl)amino]ethyl}azetiden-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1-methylethyl)amino]methyl}azetidin-3-amine; 3-[(cyclopropylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2,2,2-trifluoroethyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- (1H-imidazol-1-ylmethyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1-dimethylethyl)amino]methyl}azetidin-3-ol; 3-[(cyclopentylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N- (2,3-dihydroxypropyl)-3-hydroxyazetidine-3-carboxamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- (1H-1,2,3-triazol-1-ylmethyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2,2-dimethylpropyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(propylamino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-methylpropyl)amino]methyl}azetidin-3-ol; 3-{[(cyclopropylmethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(phenylmethyl)amino]methyl}azetidin-3-ol; 3-{[(cyclohexylmethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-[(butylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(1-ethylpyrrolidin-2-yl)methyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-hydroxyethyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(dimethylamino)ethyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-hydroxy-1,1-dimethylethyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(4-methylphenyl)ethyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(prop-2-en-1-ylamino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(2,3-dihydro-1H-inden-2-ylamino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(tetrahydrofuran-2-ylmethyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(tetrahydro-2H-pyran-4-yl)ethyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(1S,2S)-2-hydroxycyclopentyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1-dimethylprop-2-yn-1-yl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(3-pyrrolidin-1-ylpropyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1,2-dimethylpropyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[1-methyl-2-(methyloxy)ethyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[3-(ethyloxy)propyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1-ethylpropyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(3,3-dimethylbutyl)amino]methyl}azetidin-3-ol; ethyl 4-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]methyl}amino)piperidine-1-carboxylate; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(3-methylbutyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(ethyloxy)ethyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[3-(dimethylamino)propyl]amino}methyl)azetidin-3-ol; 3-[(cyclobutylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-({[3-(diethylamino)propyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro- 4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[3-(1H-imidazol-1-yl)propyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(methylthio)ethyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[1-(phenylmethyl)piperidin-4-yl]amino}methyl)azetidin-3-ol; 3-({[2,2-bis(methyloxy)ethyl]amino}methyl)-1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1,3,3-tetramethylbutyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1-dimethylpropyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(2,3-dihydro-1H-inden-1-ylamino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [({2-[(phenylmethyl)oxy]cyclopentyl}amino)methyl]azetidin-3-ol; 3-{[(3-amino-2-hydroxypropyl)amino]methyl}-1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-hydroxy-1-(phenylmethyl)ethyl]amino}methyl)azetidin-3-ol; 3-[(cyclooctylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-{[(1-cyclohexylethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-[(cycloheptylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-pyridin-3-ylethyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[3-(methylthio)propyl]amino}methyl)azetidin-3-ol; N-cyclohexyl-N~2~-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-2- methylalaninamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(3-hydroxypropyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-pyridin-4-ylethyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[1-(phenylmethyl)pyrrolidin-3-yl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(2-thienyl)ethyl]amino}methyl)azetidin-3-ol; 3-[({2-[bis(1-methylethyl)amino]ethyl}amino)methyl]-1-({3,4-difluoro-2- [(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(phenyloxy)ethyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(phenylamino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-hydroxypropyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [({2-[(1-methylethyl)oxy]ethyl}amino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1-ethylpiperidin-3-yl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(methyloxy)ethyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1- nitropropyl)azetidin-3-ol; 3-(1-aminoethyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(1-methylpiperidin-4-yl)methyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[4-(dimethylamino)butyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-furan-2-ylethyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1- [(1,1-dimethylethyl)amino]ethyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-ethylbutyl)amino]methyl}azetidin-3-ol; 1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}pyrrolidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({(2S)-2-[(methyloxy)methyl]pyrrolidin-1-yl}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-hydroxyphenyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(4-hydroxyphenyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(3-hydroxyphenyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(phenyloxy)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1r,3r,5R,7R)-tricyclo[3.3.1.1^(3,7)]dec-2-ylamino]methyl}azetidin-3-ol; 3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}amino)propane-1,2-diol; N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}-L-alanine; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(phenylthio)methyl]azetidin-3-ol; N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}-D-alanine; methyl N-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]methyl}alaninate; 3-[({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}amino)oxy]propane-1,2-diol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1-methylbutyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1-methylpropyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-methylbutyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(pentylamino)methyl]azetidin-3-ol; 3-[(cyclohexylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1- (ethylamino)ethyl]azetidin-3-ol; 3-[(azepan-3-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(dimethylamino)-1-methylethyl]amino}methyl)azetidin-3-ol; N-cyclopropyl-1-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]methyl}amino)cyclopentanecarboxamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[2-(2,3-dihydro-1H-indol-3-yl)ethyl]amino}methyl)azetidin-3-ol; N~2~-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-N- ethyl-2-methylalaninamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2- methylhydrazino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(hydroxyamino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(methyloxy)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(ethyloxy)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1- (ethylamino)propyl]azetidin-3-ol; 3-[(azetidin-3-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(1,3-thiazol-2-ylamino)methyl]azetidin-3-ol; 1,1-dimethylethyl [3-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]methyl}amino)propyl]carbamate; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(pyrrolidin-2-ylmethyl)amino]methyl}azetidin-3-ol; 1,1-dimethylethyl 4-[({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]methyl}amino)methyl]piperidine-1-carboxylate; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(2-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(3-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(4-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(4-hydroxybutyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-hydroxyethyl)oxy]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(1S,2S)-2-hydroxycyclohexyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(1,1-dimethyl-2-pyrrolidin-1-ylethyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(1-methyl-1H-imidazol-4-yl)methyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(1-methyl-1H-imidazol-5-yl)methyl]amino}methyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[(2S)-2-(methyloxy)cyclopentyl]amino}methyl)azetidin-3-ol; 3-{[1,1′-bi(cyclohexyl)-2-ylamino]methyl}-1-({3,4-difluoro-2-[(2-fluoro- 4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[3-(methyloxy)phenyl]amino}methyl)azetidin-3-ol; 1-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}amino)cyclopentanecarboxylic acid; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(4-fluorophenyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(1,3,5-triazin-2-ylamino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(trans-4-hydroxycyclohexyl)amino]methyl}azetidin-3-ol; 3-[(cyclopent-3-en-1-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; N-[4-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]methyl}amino)phenyl]acetamide; N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)phenyl]acetamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1- methylpyrrolidin-2-yl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(1H-1,2,4-triazol-3-ylamino)methyl]azetidin-3-ol; 3-[1-(diethylamino)propyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}amino)-5-(hydroxymethyl)cyclopentane- 1,2-diol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- piperidin-2-ylazetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(3-fluorophenyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1- methylpiperidin-2-yl)azetidin-3-ol; 1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}guanidine; 1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}-3-nitroguanidine; N-{1-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]ethyl}acetamide; (2R)—N-{1-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}-3,3,3- trifluoro-2-(methyloxy)-2-phenylpropanamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(piperidin-4-ylmethyl)amino]methyl}azetidin-3-ol; 3-{[(3-aminopropyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [({[2-(4-methylpiperazin-1-yl)phenyl]methyl}amino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-hydroxycyclohexyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2,2,3,3,3-pentafluoropropyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(3,3,3-trifluoropropyl)amino]methyl}azetidin-3-ol; N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]methyl}amino)phenyl]methanesulfonamide; N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}methanesulfonamide; 3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}amino)-1H-pyrazol-5-ol; (1R,2S)-4-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]methyl}amino)cyclopentane-1,2-diol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[1-(hydroxymethyl)cyclohexyl]amino}methyl)azetidin-3-ol; 3-{[(3-chlorophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-{[(4-chlorophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-[(5-amino-3-methyl-1H-pyrazol-1-yl)methyl]-1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(5-methyl-1H-pyrazol-3-yl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1- ethylpyrrolidin-2-yl)azetidin-3-ol; (2R)—N-{(1S)-1-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}-3,3,3- trifluoro-2-(methyloxy)-2-phenylpropanamide; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[4-(methyloxy)phenyl]amino}methyl)azetidin-3-ol; 3-(1-amino-2-methylpropyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-{[(4-aminophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-hydroxy-2-methylcyclopentyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1- [(4-hydroxycyclohexyl)amino]ethyl}azetidin-3-ol; methyl (2xi)-2-deoxy-2-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]methyl}amino)-beta-D-arabino-hexopyranoside; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- pyridin-2-ylazetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- ({[1-(hydroxymethyl)cyclopentyl]amino}methyl)azetidin-3-ol; 1-cyano-3-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]methyl}guanidine; 6-({3-[(ethylamino)methyl]-3-fluoroazetidin-1-yl}carbonyl)-2,3-difluoro- N-(2-fluoro-4-iodophenyl)aniline; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1- nitroethyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(3-fluoro-4-hydroxyphenyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- {[(2-fluoro-4-hydroxyphenyl)amino]methyl}azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1- (methylamino)ethyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- (1H-imidazol-2-yl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- (1H-pyrrol-2-yl)azetidin-3-ol; N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}benzenecarboximidamide; 3-({[(E)-1-amino-2-nitroethenyl]amino}methyl)-1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1- methyl-1-nitroethyl)azetidin-3-ol; 3-(1-amino-1-methylethyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-[(1H-benzimidazol-2-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(1H-imidazol-2-ylamino)methyl]azetidin-3-ol; methyl {1-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3- yl]ethyl}carbamate; 3-(1H-benzimidazol-2-yl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1- (dimethylamino)ethyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(pyrimidin-2-ylamino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(pyridin-2-ylamino)methyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1- methyl-1H-imidazol-2-yl)azetidin-3-ol; 3-(1-aminobutyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-[amino(phenyl)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(5- methyl-1H-imidazol-2-yl)azetidin-3-ol; 1,1-dimethylethyl (2S)-2-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1- carboxylate; 3-(1-amino-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- (1H-imidazol-2-ylmethyl)azetidin-3-ol; 3-(1-aminocyclopentyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-(2-aminocyclohexyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 3-(2-aminocyclopentyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(3- methyl-1-nitrobutyl)azetidin-3-ol; 3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(1S,2S)-2-hydroxycyclohexyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(1S,2R)-2-hydroxycyclohexyl]azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(6- methylpiperidin-2-yl)azetidin-3-ol; 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- piperazin-2-ylazetidin-3-ol; (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(trans)-2-hydroxycyclohexyl]azetidin-3-ol; (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(cis)-2-hydroxycyclohexyl]azetidin-3-ol; and 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(1S)-1-(methylamino)ethyl]azetidin-3-ol; or a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer thereof, and optionally as a pharmaceutically acceptable salt or hydrate thereof.


4. The method of claim 3 where the one or more chemotherapeutic agent(s) is rapamycin.
 5. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 6. The method of claim 3 where the compound is (R)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 7. The method of claim 3 where the compound is (s)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 8. The method of claim 3 where the compound is (3-(1-aminopropyl)-3-hydroxyazetidin-1-yl)(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)methanone, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 9. The method of claim 3 where the compound is (R)-(3-(1-aminopropyl)-3-hydroxyazetidin-1-yl)(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)methanone, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 10. The method of claim 3 where the compound is (S)-(3-(1-aminopropyl)-3-hydroxyazetidin-1-yl)(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)methanone, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 11. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(methylamino)ethyl]azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 12. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 13. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[piperidin-2-yl]azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 14. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 15. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 16. The method of claim 3 where the compound is (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(cis)-2-hydroxycyclohexyl]azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 17. The method of claim 3 where the compound is (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(trans)-2-hydroxycyclohexyl]azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 18. The method of claim 3 where the compound is 3-(1-aminoethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 19. The method of claim 3 where the compound is 3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 20. The method of claim 3 where the compound is 3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 21. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(pyrrolidin-1-ylmethyl)azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 22. The method of claim 3 where the compound is 1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl piperidin-4-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 23. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methylazetidin-3-amine, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 24. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(methyloxy)amino]methyl}azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 25. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-methylpyrrolidin-2-yl)azetidin-3-ol, optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 26. The method of claim 3 where the compound is 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol optionally as a pharmaceutically acceptable salt thereof and additionally optionally as a pharmaceutical composition thereof.
 27. The method of claim 1 where treating cancer comprises inhibiting cancer, relieving cancer, or inhibiting and relieving cancer. 